Capturing Relevant Capturing Relevant Patient Toxicity in Patient Toxicity in CAT (Cancer Associated CAT (Cancer Associated Thrombosis) Thrombosis) Anthony Maraveyas Anthony Maraveyas FRCP, PhD FRCP, PhD HULL YORK MEDICAL SCHOOL HULL YORK MEDICAL SCHOOL 3 3 RD RD TRAD-ALLIANCE TRAD-ALLIANCE CONFERENCE CONFERENCE YORK 2013 YORK 2013
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Capturing Relevant Patient Toxicity in CAT (Cancer Associated Thrombosis) Anthony Maraveyas FRCP, PhD HULL YORK MEDICAL SCHOOL 3 RD TRAD-ALLIANCE CONFERENCE.
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Capturing Relevant Capturing Relevant Patient Toxicity in CAT Patient Toxicity in CAT
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
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
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
Inadequate Recognition of clinical Inadequate Recognition of clinical impactimpact
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
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 clinical Inadequate Recognition of clinical impactimpact
Inadequate recognition of Inadequate recognition of ‘additional-impact’ from Cancer ‘additional-impact’ from Cancer Treatments Treatments Erythropoietin data ?Erythropoietin data ?
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
‘‘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?
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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?
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
Inadequate Recognition of clinical Inadequate Recognition of clinical impactimpact
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
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?
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%)
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
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
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
Follow-up MethodologyFollow-up Methodology
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 domino-effect?VTE domino-effect?
Maraveyas A. & Johnson M. BJC (2009) 100: 1837-1841
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
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.
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