Capturing Relevant Patient Toxicity in CAT (Cancer Associated Thrombosis) Anthony Maraveyas FRCP, PhD HULL YORK MEDICAL SCHOOL 3 RD TRAD-ALLIANCE CONFERENCE

Capturing Relevant Capturing Relevant Patient Toxicity in CAT Patient Toxicity in CAT

(Cancer Associated (Cancer Associated Thrombosis)Thrombosis)

Anthony Maraveyas Anthony Maraveyas FRCP, PhDFRCP, PhD HULL YORK MEDICAL SCHOOLHULL YORK MEDICAL SCHOOL

33RDRD TRAD-ALLIANCE TRAD-ALLIANCE CONFERENCECONFERENCE

YORK 2013YORK 2013

DisclosuresDisclosures

ConsultancyConsultancy Pfizer (Dalteparin)Pfizer (Dalteparin) Leo (Tinzaparin)Leo (Tinzaparin) Sanofi (Semuloparin)Sanofi (Semuloparin)

GrantGrant Pfizer/PharmaciaPfizer/Pharmacia

CAT and ToxicityCAT and Toxicity Capturing VTE (DVT and AT) as a Capturing VTE (DVT and AT) as a

toxicity of Cancer Treatmenttoxicity of Cancer Treatment Recognising the clinical impactRecognising the clinical impact Attributing CausalityAttributing Causality

Relevance of Toxicity of anti-coagulants Relevance of Toxicity of anti-coagulants in the Palliative cancer patientin the Palliative cancer patient Scoring system of main toxicity (Bleeding)Scoring system of main toxicity (Bleeding) Scoring and impact of ‘trivial’ bleedingScoring and impact of ‘trivial’ bleeding

VTE = venous thromboembolism.

The ChallengeThe Challenge

50% of DVT at diagnosis harbor PE50% of DVT at diagnosis harbor PE Up to 60% are Up to 60% are asymptomaticasymptomatic

DVT is not diagnosed more than 60% of DVT is not diagnosed more than 60% of patients who have a DVT and malignancypatients who have a DVT and malignancy

‘‘Practically Undiagnosable condition’Practically Undiagnosable condition’

Cronin et al . AJR 189(1):162-70 2007Ogren et al. Thr. Haemost 95: 541-5 2006

Correct Pre-mortem Diagnosis Of Pulmonary Embolism

Chronology of postmortem study

% Correct pre-mortem diagnosis

1950s 1973 – 19771980 – 19841985 – 1989 1991 – 1996

11-1230323245

Cronin et al . AJR 189(1):162-70 2007

New symptoms 78 58.4Worsening Symptoms

27 19.9

SOB 67 49.3Fatigue 103 75.7Haemoptysis 4 2.9Chest Pain 16 11.8Limb oedema 52 38.2

HEY NHS-Trust i-PE Database

136 Patients with Cancer and incidental PE

42% of patients had no new symptoms

Bozas et al in preparation

The ChallengeThe Challenge

50% of DVT at diagnosis harbor PE50% of DVT at diagnosis harbor PE Up to 60% are Up to 60% are asymptomaticasymptomatic

DVT is not diagnosed more than 60% of DVT is not diagnosed more than 60% of patients who have a DVT and malignancypatients who have a DVT and malignancy

‘‘Practically Undiagnosable condition’Practically Undiagnosable condition’ See no Evil Report No EvilSee no Evil Report No Evil

Cronin et al . AJR 189(1):162-70 2007Ogren et al. Thr. Haemost 95: 541-5 2006

‘‘Clinical Method’ Clinical Method’ LimitationsLimitations

Limitations – Masking VTELimitations – Masking VTE Inadequate Recognition of clinical impactInadequate Recognition of clinical impact Inadequate recognition of ‘additional-Inadequate recognition of ‘additional-

impact’ from intervention -Cancer impact’ from intervention -Cancer Treatments- Treatments-

Risk obscured by discrepant demographics Risk obscured by discrepant demographics of Trial sample vs. Real world populationsof Trial sample vs. Real world populations

Reporting methodologyReporting methodology Attributing causalityAttributing causality

‘‘Clinical Method’ Clinical Method’ limitationslimitations

Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841


Inadequate Recognition of clinical Inadequate Recognition of clinical impactimpact


Incidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer StageIncidence of VTE and Colon Cancer Stage

White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40White RH et al. Thrombosis Research 120 Suppl. 2 (2007) S29-40

Days after Cancer DiagnosisDays after Cancer Diagnosis

Inci

denc

e of

VT

E (

%)

Inci

denc

e of

VT

E (

%)

0 50 100 150 200 250 300 350 4000 50 100 150 200 250 300 350 400

7%7%

6%6%

5%5%

4%4%

3%3%

2%2%

1%1%

0%0%

Local Regional RemoteLocal Regional Remote

Kaplan-Meier plots comparing the incidence of death after venous thromboembolism (VTE) with the incidence of death in matched

patients who never developed VTE

Alcalay, A. et al. J Clin Oncol; 24:1112-1118 2006


Inadequate recognition of Inadequate recognition of ‘additional-impact’ from Cancer ‘additional-impact’ from Cancer Treatments Treatments Erythropoietin data ?Erythropoietin data ?



‘‘Clinical Method’ limitations -Clinical Method’ limitations -VTE rates in EPO VTE rates in EPO studiesstudies

Bennett C.L. et al JAMA (2008) 299: 914–924

‘‘Clinical Method’ limitations- Clinical Method’ limitations- Mortality rates in Mortality rates in EPO studiesEPO studies

Bennett C.L. et al JAMA (2008) 299: 914–924

Inadequate Recognition of clinical impactInadequate Recognition of clinical impact Inadequate recognition of ‘additional-impact’ Inadequate recognition of ‘additional-impact’

from Cancer Treatmentsfrom Cancer Treatments Erythropoietin data ?Erythropoietin data ? New agents?New agents?

AvastinAvastin SunitinibSunitinib SorafenibSorafenib AxitinibAxitinib PazopanibPazopanib VEGF trap (Aflibercept)VEGF trap (Aflibercept) Anti-EGF strategiesAnti-EGF strategies



Nalluri, S. R. et al. JAMA 2008;300:2277-2285.

Relative Risk = 1.33 [95% CI: 1.13 – 1.56]Absolute Risk Increase: 2.2% [95% CI: 1.1% -

3.3%]

Bevacizumab (Avastin) Increases Risk of Bevacizumab (Avastin) Increases Risk of Symptomatic VTE by 33% vs ControlsSymptomatic VTE by 33% vs Controls

Arterial Thromboembolic Events (ATE) in RCTs with TKIs

(Sutent & Sorafenib)

Choueiri T K et al. JCO 2010;28:2280-2285

Study or Subgroup1.1.1 VTEs anti-EGFR MoAbs

Burtness 2005Hecht 2009Tol 2009Pirker 2010Okines 2010Peeters 2010Vermorken 2010Douillard 2010Subtotal (95% CI)

Total eventsHeterogeneity: Chi² = 3.70, df = 7 (P = 0.81); I² = 0%Test for overall effect: Z = 2.58 (P = 0.010)

1.1.2 VTEs anti-EGFR TKIs

Gatzmeier 2007Herbst 2007Crino' 2008Subtotal (95% CI)

Total eventsHeterogeneity: Chi² = 0.31, df = 1 (P = 0.58); I² = 0%Test for overall effect: Z = 1.36 (P = 0.17)

Total (95% CI)

Total eventsHeterogeneity: Chi² = 4.33, df = 9 (P = 0.89); I² = 0%Test for overall effect: Z = 2.88 (P = 0.004)Test for subgroup differences: Chi² = 0.28, df = 1 (P = 0.60), I² = 0%

Events

35430230

221916

167

1900

19

186

Total

5840736654813

539325539

2795

5803994

619

3414

Events

14625161

121013

124

1115

12

136

Total

5839736656216

540325545

2809

5798196

660

3469

Weight

0.7%34.1%18.3%11.6%1.0%8.8%7.3%9.5%

91.2%

8.1%0.7%0.0%8.8%

100.0%

M-H, Fixed, 95% CI

3.00 [0.32, 28.00]1.15 [0.79, 1.65]1.20 [0.72, 2.00]1.47 [0.79, 2.76]0.40 [0.02, 9.18]1.84 [0.92, 3.67]1.90 [0.90, 4.02]1.24 [0.60, 2.56]1.34 [1.07, 1.68]

1.72 [0.83, 3.59]0.68 [0.03, 16.40]0.09 [0.01, 1.66]1.64 [0.81, 3.34]

1.37 [1.11, 1.69]

Year

20052009200920102010201020102010

200720072008

Experimental Control Risk Ratio Risk RatioM-H, Fixed, 95% CI

0.02 0.1 1 10 50Favours control Favours experimental

Arterial Thromboembolic Events (ATE) in RCTs with EGFR inhibitors

(Mostly with chemotherapy)

Petrelli F. et al Ann Oncol. 2012 Jul;23(7):1672-9


Risk obscured by discrepant Risk obscured by discrepant demographics of Trial sample vs demographics of Trial sample vs Real World populationsReal World populations AgeAge

Mean age of trial patients commonly 60-65Mean age of trial patients commonly 60-65 Mean age community population treated Mean age community population treated

70-7570-75


‘‘Clinical Method’ limitationsClinical Method’ limitations ‘‘Arterial ThromboembolismArterial Thromboembolism’’

0

4

8

12

16

20

Chemotherapy plus Avastin Chemotherapy alone

ATE R

ate

(%

)

Total cohort n=963 bevn=872 ctrl

Age ≥65 yr n=339 bevn=279 ctrl

No risk factors

n=602 bevn=490 ctrl

Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239.


Risk obscured by discrepant Risk obscured by discrepant demographics of Trial sample vs demographics of Trial sample vs Community populationsCommunity populations AgeAge

Mean age of trial patients commonly 60-65Mean age of trial patients commonly 60-65 Mean age community population treated Mean age community population treated

70-7570-75 History of VTE (any)History of VTE (any)

How many of us take a proper thrombosis How many of us take a proper thrombosis history?history?


0

4

8

12

16

20

Chemotherapy* plus bevacizumab Chemotherapy* alone (control group)

ATE R

ate

(%

)

Total cohort n=963 bevn=872 ctrl

ATE history + age ≥65 yrn=67 bevn=46 ctrl

ATE history n=89 bevn=59 ctrl

Age ≥65 yr n=339 bevn=279 ctrl

No risk factors

n=602 bevn=490 ctrl

Scappaticci FA, et al. J Natl Cancer Inst. 2007;99:1232-1239.

*Irinotecan, capecitabine, fluorouracil and leucovorin, or carboplatin/paclitaxel


‘‘Arterial ThromboembolismArterial Thromboembolism’’


Inadequate recognition of Inadequate recognition of ‘additional-impact’ from intervention ‘additional-impact’ from intervention

Risk obscured by discrepant Risk obscured by discrepant demographics of Trial sample vs demographics of Trial sample vs Community populationsCommunity populations

Reporting MethodologyReporting Methodology



Reporting MethodologyReporting Methodology Standards of Care set by trialsStandards of Care set by trials

Grading toolGrading tool



Grade 1Grade 1 Grade Grade 22

Grade Grade 33

Grade 4Grade 4 Grade Grade 55

Thromboembolism - Deep Vein Thrombosis or Cardiac thrombosis; intervention (e.g. anticaoagulation, lysis, filter, invasive procedure) NOT indicated

Deep Vein Thrombosis or Cardiac thrombosis; intervention (e.g. anticaoagulation, lysis, filter, invasive procedure) INDICATED

Embolic event including pulmonary embolism or life-threatening thrombus

Death

CTCAE Grading of Diagnosed VTE


ISTH working Group ISTH working Group Recommendations 2012Recommendations 2012

Arterial vs. VenousArterial vs. Venous Deep vs. SuperficialDeep vs. Superficial Regional locationRegional location

Naming of Vessel (Portal, Femoral, Cerebral etc)Naming of Vessel (Portal, Femoral, Cerebral etc) Thrombotic Burden (Segmental vs. Sub-Thrombotic Burden (Segmental vs. Sub-

segmental PE)segmental PE) Catheter vs. Non-catheter relatedCatheter vs. Non-catheter related Symptomatic Vs IncidentalSymptomatic Vs Incidental Appropriate statistical methodologyAppropriate statistical methodology

Competing risk analysisCompeting risk analysis

Carrier M. et al J Thromb Haemost. 2012 10: 2599-601

Reporting MethodologyReporting MethodologyStandards of Care set by trialsStandards of Care set by trials

Grading toolGrading toolSAE -AESAE -AE

IdentificationIdentification



VTE in APC TrialsVTE in APC Trials 19 phase III randomised trials19 phase III randomised trials 6212 patients 6212 patients 1447 (23.3%) died in the first three-month 1447 (23.3%) died in the first three-month

period.period. PresumedPresumed progressive cancer in 1407 (97.2%) progressive cancer in 1407 (97.2%) Cause of death was reported in only 40 cases Cause of death was reported in only 40 cases

(2.8%).(2.8%). Progressive cancer 21 (52.5%) Progressive cancer 21 (52.5%) Infection (20%) Infection (20%) ‘‘Cancer-related complications’ (10%)Cancer-related complications’ (10%) ARF (5%).ARF (5%). VTE (5%)VTE (5%)

Sgouros J, Maraveyas A. Acta Oncologica, 47(3): 2008, 337 – 346.Sgouros J, Maraveyas A. Acta Oncologica, 47(3): 2008, 337 – 346.

Of 1447 patients who died in 12 Of 1447 patients who died in 12 weeks from commencing trialweeks from commencing trial 2 (!) Were reported as having died of a 2 (!) Were reported as having died of a

VTE VTE (0.1%) (0.1%)

Not Recognized or Not Not Recognized or Not Reported?Reported?

Sgouros J, Maraveyas A. Acta Oncologica, 47(3): 2008, 337 – 346.Sgouros J, Maraveyas A. Acta Oncologica, 47(3): 2008, 337 – 346.

PA.3 TrialPA.3 TrialGem-Erlotinib Vs GemGem-Erlotinib Vs Gem

Initial publication had no mention of Initial publication had no mention of VTEVTE

‘‘Correspondence request’Correspondence request’ 14% VTE in each arm14% VTE in each arm

40/245 Gem Erlotinib40/245 Gem Erlotinib 41/243 Gem SA41/243 Gem SA

Moore MJ, et al: J Clin Oncol 25:1960-1966, 2007

GISCAD RCT-Colorectal GISCAD RCT-Colorectal CancerCancer

During the trial the Co-ordinating During the trial the Co-ordinating centre had VTE reported by the centre had VTE reported by the investigators investigators 2/266 (0.7%) 2/266 (0.7%)

Retrospective Trial Monitoring Retrospective Trial Monitoring revealedrevealed

27/266 (10.1%)27/266 (10.1%)

14-fold difference14-fold difference

Mandalà M et al. Eur J Cancer. 2009 Jan;45(1):65-73

Active ascertainment of Active ascertainment of Thrombosis Thrombosis can produce an up to can produce an up to 55-fold greater incidence than 55-fold greater incidence than passive ascertainmentpassive ascertainment Reynolds M.W. et al Current Medical Research Reynolds M.W. et al Current Medical Research

and Opinions (2008) 24: 497-505 and Opinions (2008) 24: 497-505

Not Recognized or Not Not Recognized or Not Reported?Reported?

Reporting MethodologyReporting MethodologyStandards of Care set by trialsStandards of Care set by trials

Grading toolGrading toolSAE-AE SAE-AE

IdentificationIdentification Attributing CausalityAttributing Causality



Attributing CausalityAttributing Causality

Long term morbidity and outcome Long term morbidity and outcome compromise?compromise? CCF after MICCF after MI Paresis and aftermath after CVAParesis and aftermath after CVA Cancer treatment termination due to Cancer treatment termination due to

MI/CVAMI/CVA Pulmonary insufficiency from chronic Pulmonary insufficiency from chronic

PE effectsPE effects


VTE-Time from VTE-Time from RandomizationRandomization

Dalteparin

Control

0 50 100 150 200 250 300

Days

(794 Days)(PM) (PM)

Clinical non-lethal VTELethal VTEIncidental VTE

Sudden death VTE-suspectedPM= Post-mortem

VTE-Time from VTE-Time from RandomizationRandomization

Dalteparin

Control

0 50 100 150 200 250 300

Days

(794 Days)

CVAs

Maraveyas et al EJC 2012 48: 1283-1292

Follow-up MethodologyFollow-up Methodology



PE effectsPE effects


Follow-up MethodologyFollow-up Methodology



PE effectsPE effects VTE domino-effect?VTE domino-effect?


VTE ‘Domino’VTE ‘Domino’

CV EventCV Event 1 Year RR1 Year RR 2-20 Year 2-20 Year RRRR

Acute MIAcute MI 2.62.6 1.31.3

StrokeStroke 2.92.9 1.31.3

Sorensen HT. Lancet 2007; 370: 1773-1779

Relative Risk (RR) of CV Events in PE PatientsRelative Risk (RR) of CV Events in PE Patients

VTE-‘Perception VTE-‘Perception Gap’Gap’

(A.A. Turpie)(A.A. Turpie)Clinically non-recognized Clinically non-recognized

VTE –syndrome does VTE –syndrome does

not meannot mean clinically insignificant VTEclinically insignificant VTE

CAT-treatment CAT-treatment (Prophylaxis) (Prophylaxis)

Related ToxicityRelated Toxicity

BleedingBleeding

5

10

15

20

2 4 6 8 10 12

%

Months

Cumulative Incidence Of Major Cumulative Incidence Of Major Bleeding On WarfarinBleeding 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

n=59

CapecitabineTamoxifenSorafenibSunitinib

Twilley C. H. 2002

CLOT: Cancer/VTE TrialCLOT: Cancer/VTE Trial

CANCER PATIENTS WITH ACUTE DVT or

PE

Randomization

Oral Anticoagulant

Dalteparin

[N = 677]

► Primary Endpoints: Recurrent VTE and Bleeding

► Secondary Endpoint: Survival

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Dalteparin

Dalteparin

Treatment of Treatment of Cancer-Associated VTECancer-Associated VTE

StudyStudy DesignDesign

Length Length of of

TherapTherapyy

(Months(Months))

NNRecurrenRecurren

t VTEt VTE (%)(%)

Major Major BleedinBleedin

gg

(%)(%)

DeathDeath

(%)(%)

CLOT Trial

(Lee 2003)

Dalteparin

OAC

6 336

336

9

17

6

4

39

41

CANTHENOX

(Meyer 2002)

Enoxaparin

OAC

3 67

71

11

21

7

16

11

23

LITE

(Hull 2006)

Tinzaparin

OAC

3 100

100

7

16

7

7

47

47

ONCENOX

(Deitcher ISTH 2003)

Enox (Low)

Enox (High)

OAC

6 32

36

34

3.4

3.1

6.7

NS

NS0.044

NS

NS0.002

NS

NS

NR

0.09

0.030.09

Retrospective cohort Retrospective cohort studiesstudies

Bleeding was reported as major or Bleeding was reported as major or ‘clinically significant’ ‘clinically significant’ in 11in 1135%; minor in 35%; minor in 252532%32% Up to five-fold greater than recorded in RCTsUp to five-fold greater than recorded in RCTs

Risk of bleeding associated with Risk of bleeding associated with increasing age and chemotherapy in one increasing age and chemotherapy in one study.study.

In another, bleeding unrelated to In another, bleeding unrelated to thrombocytopenia, abnormal blood thrombocytopenia, abnormal blood coagulation or metastases.coagulation or metastases.

Noble S. et al Lancet Oncol. 2008; 9: 577-84

Scoring Hemorrhagic Scoring Hemorrhagic Event SeverityEvent Severity

ISTH Scoring (ISTH, 2005) ISTH Scoring (ISTH, 2005) ‘‘Severe’-MajorSevere’-Major

Fall in haemoglobin of 2 g/dL or transfusion Fall in haemoglobin of 2 g/dL or transfusion of 2 or more units of blood, bleeding that is of 2 or more units of blood, bleeding that is symptomatic in a critical organ (intra-symptomatic in a critical organ (intra-cranial, intra-spinal, intra-ocular, cranial, intra-spinal, intra-ocular, retroperitoneal, intra-articular or peri-retroperitoneal, intra-articular or peri-cardiac, or intra-muscular with cardiac, or intra-muscular with compartment syndrome) or fatal compartment syndrome) or fatal

‘‘Non severe’Non severe’

Condensed version of the bleeding assessment tool.

O'Brien S H Hematology 2012;2012:152-156

Relevant toxicity to a Relevant toxicity to a palliative care patientpalliative care patient

Current tools irrelevant for the Current tools irrelevant for the conventional palliative care patient conventional palliative care patient

Role of the clinician’s views (DD project)Role of the clinician’s views (DD project) What we call ‘low grade’ bleeding may have What we call ‘low grade’ bleeding may have

significant impact on patients who have significant impact on patients who have EoL needs and goalsEoL needs and goals

Qualitative research is needed to Qualitative research is needed to understand the patient and carer issues understand the patient and carer issues betterbetter ? Develop a relevant scoring tool? Develop a relevant scoring tool

Thank youThank you

[email protected]

Documents

Capturing Relevant Patient Toxicity in CAT (Cancer Associated Thrombosis) Anthony Maraveyas FRCP, PhD HULL YORK MEDICAL SCHOOL 3 RD TRAD-ALLIANCE CONFERENCE