Survivor: Hodgkin Survivor: Hodgkin Aaron T. Gerds, MD, MS K Scott Baker MD MS

Survivor: Hodgkin
Survivor: Hodgkin
Aaron T. Gerds, MD, MS
Hematology‐Oncology Fellow
University of Washington School of Medicine
Discussant:
K Scott Baker MD MS
K. Scott Baker, MD, MS
Professor, Department of Pediatrics, UW
Medical Director, Pediatric Blood and Marrow Transplant Program
Seattle Cancer Care Alliance/Seattle Children’s Hospital
Member, CRD, Fred Hutchinson Cancer Research Center
Hodgkin lymphoma closing in on a cure for all…
f
ll
• 70‐95%
70 95% cured up front
cured up front
• Response adapted (PET) approach may improve outcomes and reduce toxicity
improve outcomes and reduce toxicity
• Auto transpalnt can cure ~40%
• Non‐ablative allo‐HCT may cure ~30%
• Novel agents
g
– Control relapsed disease
– Earlier use may yield more initial cures
Earlier use may yield more initial cures
Slide courtesy of A. Gopal, MD
Progress in HL
Progress in HL
1.0
BEACOPP escalated
(1993–2004)
BEACOPP baseline
(1993–1998)
Prrobability
0.8
COPP/ABVD
(1988 1993)
(1988–1993)
0.6
Stanford V, CLVP/EVA
04
0.4
No treatment (1940)
0.2
0.0
ABVD?
Only alkylating agents (1965)
0
1
2
3
4
5
6
Overall Survival (y)
Figure courtesy of O. Press, MD, PhD
7
8
9
10
Age‐Specific Incidence and Death Rates, UK, 2008
Iccidence pe
er 100,000
6.0
5.0
4.0
3.0
Female Death Rate
Male Death Rate
2.0
Female Incidence
Male Incidence
1.0
0.0
Age
Cancer Research UK (2008). CancerStats report – Hodgkin Lymphoma UK, Cancer Research UK.
Case
History of present illness
History of present illness
A 21 year old male presented with a 3 hour A
21 year old male presented with a 3 hour
history of substernal chest pain radiating to the left arm and jaw
The pain began during strenuous exercise and The
pain began during strenuous exercise and
was not relieved with rest. He had no dyspnea, lightheadedness, nausea, vomiting, or diaphoresis.
vomiting, or diaphoresis.
Past medical history
Past medical history
Stage IIA Hodgkin’s disease of the mediastinum diagnosed in 1996 – 6 cycles of COPP‐ABV – 2,100 cGy
2,100 cGy mantle RT
mantle RT
Recurrence in November 1999 – 4 cycles of ICE – Autologous PBSCT in April 2000
– 3000cGy of mediastinal
y
RT
FVL heterozygote, h/o line thrombus Meidcation, family, and social history
Meidcation, family, and social history
Medications: None
ed cat o s: o e
Family History
Family History
– Father: History of DVT – Factor V Leiden
Social Historyy
– Athletic college student – No alcohol or drugs
Examination
Vitals: BP 138/80 HR 100 RR 18 99% RA 97kg
Vitals:
BP 138/80 HR 100 RR 18 99% RA 97kg
Gen: Fit appearing male in mild distress
HEENT: No JVD, no LAD
HEENT: No JVD no LAD
CV: Tachycardic, regular rhythm, S1, S2, no murmur
Lungs: Clear
Abd
Abd:
S ft NABS
Soft, NABS, no organomegaly
l
Ext:
Warm, no edema
Laboratory and imaging
Laboratory and imaging
Troponin 91 (Normal <1.1)
Troponin 91 (Normal <1.1)
Echocardiogram
– Moderately hypokinetic anterolateral wall, EF 55%
Angiogram
– Large filling defect in the proximal LAD, small L
filli d f t i th
i l LAD
ll
apical defect consistent with possible distal embolization Hospital course
Hospital course
• Admitted
Admitted to ICU, thrombolytics
to ICU thrombolytics
• Repeat angiogram 2 days later revealed decrease in thrombus
decrease in thrombus
• Cardiac rehabilitation • Discharged on hospital day 6 • Discharge medications
g
– ASA, clopidogrel, warfarin, lisinopril, metoprolol, atorvastatin
Life after HL
Life after HL
"Today, we have learned in the agony of war y,
g y
that great power involves great responsibility. ‐FDR
1. Better understand the biological basis and clinical consequences of a cancer diagnosis and the q
g
associated therapeutic exposure
2 Propose
2.
Propose, develop, and test strategies to avoid or develop and test strategies to avoid or
minimize the adverse impact of cancer and its treatment
Common complications of HL therapy
Common complications of HL therapy
• Secondary malignancies
Seco da y a g a c es
– Up to 20% in 20 yr (breast, lung, MDS/AML, NHL)
• Cardiovascular events
– Premature coronary artery disease
– Cardiomyopathy
– Valvular disorders
• Hypothyroidism (mantle RT)
• Bleomycin lung toxicity
• Sterility (esp. MOPP, escBEACOPP)
Adverse
events after chemo + RT
Adverse events after chemo + RT
Armatage, JO. N Engl J Med. 2010 Aug 12;363(7):653‐62.
JAMA. 2010 Mar 17;303(11):1019‐20.
Because many therapies used to treat patients with cancer have cardiotoxic effects, teamwork by oncologists and cardiologists is important in preventing treatment‐related heart problems.
Cardiotoxicity incidence
• CVD incidence in 1474 survivors of HL < 41 years y
at treatment (1965‐1995)
– Median follow up of 18.7 years
• As compared to general population
A
dt
l
l ti
– SIR of MI and CHF was 3.6 and 4.8
– 35.7 excess cases of MI and 25.6 excess cases of CHF 35.7 excess cases of MI and 25.6 excess cases of CHF
per 10 000 patients/year
• Anthracyclines further increase the elevated risks of CHF and valvular disorders from mediastinal
of CHF and valvular
disorders from mediastinal
radiotherapy – HRs were 2.81 and 2.10 respectively
p
y
Aleman et al. Blood 2007;109:1878‐1886
Aleman et al. Blood 2007;109:1878‐1886
.
Angina pectoris
Angina pectoris
Aleman et al. Blood 2007;109:1878‐1886
Myocardial infarction
Myocardial infarction
Aleman et al. Blood 2007;109:1878‐1886
Cumulative incidence all CVD
Cumulative incidence all CVD
Aleman et al. Blood 2007;109:1878‐1886
Cardiotoxicity incidence
Predisposing risk factors for cardiovascular disease Predisposing
risk factors for cardiovascular disease
can be detected at higher rates in pediatric cancer survivors compared with siblings
p
g
• Survivors were …
–
–
–
–
1.9 times more likely to take medications for HTN
1
9 times more likely to take medications for HTN
1.6 times more likely to take cholesterol medication
1.7 times more likely to take medications for diabetes
1.7 times more likely to take medications for diabetes
Not more likely than their siblings to be obese
Meacham LR et al. Cancer Epidemiol Biomarkers Prev. 2010;19:170‐181
How can we predict an increased risk for How
can we predict an increased risk for
cardiovascular complication in HL patients up front before treatment?
front before treatment?
Defining populations at high‐risk for adverse D
fi i
l i
hi h i k f
d
outcomes is critical when beginning to contemplate targeted intervention approaches. l
di
i
h
• Anthracycline
Anthracycline‐induced
induced cadiotoxicity
cadiotoxicity
Traditional risk factors for anthracycline‐induced cadiotoxicity
h
l
d d d
• Therapeutic risk factors
Therapeutic risk factors
– Incidence is <10%, cumulative dose <500 mg/m2
– Approaches 36% for doses > 600 mg/m
Approaches 36% for doses > 600 mg/m2
• Clinical risk factors
– Exposed at a younger age (<5 years)
(
)
– Females > males
– Preexisting heart disease
– Chest irradiation • Increasingly
Increasingly evident that the conventionally evident that the conventionally
described clinical and therapeutic risk factors may not fully explain the wide interindividual
y p
variability in susceptibility to anthracycline‐
related cardiomyopathy. • Cardiotoxicity has been reported at cumulative exposure of less than 250 to 300 mg/m
p
g 2 in some patients, doses exceeding 1,000 mg/m2 have been tolerated well by others.
Anthracycline‐induced
Anthracycline
induced CHF
CHF
MRP1
MRP2
CBR1
CBR3
NAD(P)H oxidase subunit NCF4 Bhatia. Cancer Epidemiol Biomarkers Prev 2011;20(10):2048–67.
• 2
2,977 SNPs in 220 key drug biotransformation 977 SNPs in 220 key drug biotransformation
genes
– Discovery cohort of 156 anthracycline‐treated Discovery cohort of 156 anthracycline treated
children from British Columbia
– Replication in a second cohort of 188 children Replication in a second cohort of 188 children
from across Canada – 2nd replication of the top SNP in a third cohort of replication of the top SNP in a third cohort of
96 patients from Amsterdam, the Netherlands
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
Visscher et. al. J Clin Oncol. 2011 Oct 11. [Epub ahead of print]
HL survivor follow up
HL survivor follow up
• NCCN
NCCN guidelines recommend follow up with guidelines recommend follow up with
oncologist attune to the long‐term risks
– 2‐4 months in the first 2 years
2 4 months in the first 2 years
– Every 3‐6 months for years 3‐5
– Annually after 5 years
Annually after 5 years
Recommended follow up for CVD
Recommended follow up for CVD
• XRT
XRT‐induced
induced cardiotoxicity
cardiotoxicity occurs 5
occurs 5‐10
10 years
years
– But cardiovascular symptoms can occur at any age
• NCCN guidelines
– Baseline stress test or echo at 10 years after tx
– Annual blood pressure monitoring
– Aggressive management of CV risk factors
van Leeuwen‐Segarceanu et al. Cancer Treatment Rev 2011;37:391–403.
Robison and Demark‐Wahnefried. Cancer Epidemiol Biomarkers Prev 2011;20:1994‐1995. Th k
Thanks
Dr. Baker
D G
Dr. Gopal
l
Dr. Blau