Running on Empty:
Cardiovascular Reserve Capacity and Late Effects of Therapy in Cancer Survivorship
- Graeme J. Koelwyn,Michel Khouri,John R. Mackey,Pamela S. Douglas and
- Lee W. Jones⇓
- © 2012 by American Society of Clinical Oncology
+ Author Affiliations
- Corresponding author: Lee W. Jones, PhD, Box 3085, Duke Cancer Institute, Durham, NC 27710, USA; e-mail: lee.w.jones@duke.edu.
Seminal investigations by Frank1 and Starling2
provided the first evidence that the heart possesses inherent reserve
capacity—a key principle that is a pillar of modern
cardiology research and practice. After 150 years of
research, we now understand that cardiovascular reserve capacity (CVRC)
is determined by the integrative ability of
cross-system mechanisms (eg, neurohormonal, central, and peripheral
oxygen delivery3),
which collectively possess remarkable adaptive capacity. Sequential as
well as concurrent pathologic perturbations to either
one or more of these mechanisms are offset by initial
compensatory adaptive responses in other component systems to maintain
whole-body homeostatic regulation—a process termed
coordinated adaptation.4
Unfortunately, CVRC is finite, and continued insults ultimately lead to
overt dysfunction (eg, acute coronary syndromes,
left ventricular dysfunction). Pathologic impairments
in CVRC are etiologic in many chronic disease conditions and are thus
an integral consideration in daily practice. The
purpose of this commentary is to provide an overview of the guiding
principles
and application of CVRC in the oncology setting using
early breast cancer as an illustrative model.
Measurement of CVRC
In current oncology practice,
evaluation of CVRC is almost exclusively determined via resting
assessment of left ventricular
ejection fraction (LVEF) via echocardiography or
radionuclide angiography, typically before administration of
potentially
cardiotoxic adjuvant therapy. Using these
approaches, the incidence of heart failure with modern anthracycline-
and trastuzumab-containing
regimens is < 5%, with corresponding rates of
asymptomatic LVEF reductions between 10% and 50%.5–7
Resting LVEF, however, provides a snapshot of cardiac performance under
optimal circumstances. Moreover, in addition to being
load, rate, and contractility dependent, resting
LVEF is not a sensitive measure of early myocyte (subclinical) damage8 and is not prognostic in patients with preserved LVEF (> 50%).9 Emerging techniques such as tissue Doppler imaging,10,11 speckle-tracking strain echocardiography,12 and magnetic resonance imaging13
may provide more sensitive detection of cardiac injury, although
supporting evidence is currently limited. Impairments in
other cardiac parameters such as diastolic
relaxation and filling also occur after breast cancer treatment, despite
preserved
LVEF.14–16
The application of system stress is a hallmark method to detect subclinical myocardial impairments and coronary artery disease
(CAD).17 Both nonpharmacologic (exercise) and pharmacologic (eg, dobutamine, dipyridamole) stress are commonly applied in conjunction
with conventional imaging approaches to detect obstructive CAD.17,18 In this setting, exercise testing and determination of inotropic (contractile) reserve are independent predictors of prognosis
beyond clinical factors, coronary anatomy, and LVEF.19,20
Extending Beyond the Heart
CVRC is determined by the integrative
capacity of the cardiopulmonary system; thus it seems plausible that
therapy-induced
myocardial injury may occur in conjunction with
(mal)adaptation in other organ components. Many anticancer therapies
cause
unique and varying degrees of injury to the
cardiovascular system (ie, pulmonary-vascular/blood-skeletal muscle
axis). For
example, radiation and certain forms of systemic
therapy (eg, chemotherapy, molecularly targeted therapies) can cause
pulmonary
dysfunction, anemia, endothelial dysfunction,
and arterial stiffness and likely skeletal muscle dysfunction (eg,
reduced oxidative
phosphorylation).21–25 These direct insults occur in conjunction with indirect lifestyle perturbations (eg, physical inactivity) that synergistically
cause marked impairments in CVRC. We have termed this phenomenon the multiple-hit hypothesis.21 Hence, tools with the ability to evaluate integrated cross talk between cardiovascular organ components may arguably provide
the most accurate characterization of global (whole-body) CVRC.
To this end, incremental exercise
tolerance testing, which evaluates cardiorespiratory fitness (ie,
efficiency of the cardiopulmonary
system to deliver and use oxygen to resynthesize
ATP), is a powerful predictor of cardiovascular and all-cause mortality
in
a broad range of adult populations.26,27
Of relevance, we found that despite preserved LVEF ≥ 50%,
cardiorespiratory fitness was significantly impaired in patients
with early breast cancer a mean of 3 years after
the completion of adjuvant therapy, compared with women of the same age
without
a history of breast cancer.28
Specifically, patients reached a predicted cardiorespiratory fitness
for a particular age group (eg, 40 years) approximately
20 to 30 years earlier than age-matched women
without a history of cancer. The combination of global CVRC assessment
with
cardiac biomarkers could also provide a powerful
approach. Cardiac troponin T, troponin I, and N-terminal
pro-brain natriuretic peptide are independent predictors of
cardiovascular disease (CVD) mortality in healthy populations29,30 and of cardiotoxicity in patients with hematologic and solid malignancies.31,32
Clearly, a number of tools are
available to oncology professionals to both detect and monitor
therapy-induced cardiovascular
injury. When used appropriately, such tools
should accurately characterize CVRC and provide additional
decision-making information
beyond that provided by current established
techniques, allowing more accurate prognostication and early
intervention. Evidence-based
recommendations to guide the selection of
method(s) are not available in the oncology setting but are well
established in
cardiovascular medicine.33
For example, the American College of Cardiology/American Heart
Association recommend that CVRC evaluation of patients presenting
with heart failure include subjective
symptomatic classifications (ie, New York Heart Association functional
classification)
as well as exercise tolerance testing.33
Although guidelines are not currently available, we contend that
evaluation of CVRC should be initially considered for patients
receiving antitumor agents/regimens known to
cause cardiac damage or for those presenting with CAD risk factors that
increase
the risk of cardiotoxicity. However, anticancer
agents likely cause unique and varying degrees of injury to all
components
of the cardiovascular system; thus assessment of
CVRC could arguably be considered for all patients initiating adjuvant
therapy.
Such recommendations are not evidence based at
present, and the ideal method(s) for predicting acute and/or
late-occurring
CVD in the oncology setting has not been
established.34 Additional studies are now required to determine the feasibility, cost, and clinical importance of CVRC testing in breast
as well as other cancer populations.
Increasing Importance of Evaluating CVRC in Early Breast Cancer
The Childhood Cancer Survivor Study
(CCSS), a prospective cohort of more than 20,000 adult survivors of
childhood cancer,
has demonstrated that significant improvements
in cancer-specific survival come at the expense of considerable
increased risk
of competing causes of morbidity and mortality.35
Specifically, in comparison with a sibling comparison group, the
relative risk of congestive heart failure, CAD, and cerebrovascular
events was 15.1 (95% CI, 4.8 to 47.9), 10.4 (95%
CI, 4.1 to 25.9), and 9.3 (95% CI, 4.1 to 21.1), respectively, 25 years
after
primary diagnosis.36
The long-term follow-up (> 25 years) results highlight the prolonged
latency required from initial exposure to development
of major events. Of similar importance,
significant improvements in early detection and adjuvant therapy have
also resulted
in dramatic reductions in the risk of
cancer-specific mortality after a diagnosis of early breast cancer.37
Consequently, younger and middle-age patients with breast cancer now
have sufficient survival to be at risk for competing
mortality. Thus, is it plausible to ask whether
the CCSS experience provides a relevant benchmark to estimate the future
extent
and magnitude of cardiovascular late effects in
the estimated 2.5 million adult breast cancer survivors?
Clearly, the mechanisms of injury are
likely unique between children and adults, given that anticancer therapy
is administered
during cardiac development in the pediatric
oncology population. Nevertheless, juvenile hearts possess tremendous
reserve
capacity, which is in contrast to adult patients
with cancer, in whom anticancer therapy is generally initiated when
CVRC
is already significantly diminished because of
aging and comorbid conditions (especially in those age ≥ 65 years).38,39
As such, it could be speculated that therapy initiated in elderly
patients could cause equal or possibly accelerated manifestation
of CVD. Intriguingly, emerging evidence
indicates that CVD is now the predominant cause of mortality in the
population of
women diagnosed with early-stage breast cancer,
especially in those diagnosed at age > 50 years.40–43 Moreover, it seems that patients with breast cancer may have excess CVD risk compared with age-matched control women without
a history of cancer.44,45
It is important to remember, however, that the burden of CVD in
recently published studies reflects the management patterns
for early-stage breast cancer 15 to 20 years
ago, not those associated with modern therapeutic approaches. On one
hand, the
risk of late-occurring CVD may be lower because
of the introduction of newer radiotherapy techniques and wide
recognition
of anthracycline-induced cardiotoxicity. On the
other hand, these advances could be offset by more aggressive use of
anthracyclines
(higher doses and shorter intervals between
cycles), approval of newer adjuvant cytotoxic agents (taxane-based
regimens) and
hormonal regimens (aromatase inhibitors), and
introduction of molecularly targeted therapies (human epidermal growth
factor
receptor 2– directed therapies), all of which
have different cardiovascular safety profiles than historical regimens.
Modern
adjuvant therapy is also generally administered
for longer durations, with a growing trend toward extended adjuvant
therapy,
which increases the period of exposure and
possibly the extent of cardiovascular injury.
A conceptual model to illustrate the suspected trajectories of therapy-induced declines/recovery in CVRC, based on prior work
in early breast cancer,28,47,48 is presented in Figure 1.
As outlined, the trajectory of change in CVRC across the breast cancer
treatment continuum is contingent on the interaction
between patient CVRC at diagnosis, which is
determined by nonmodifiable (eg, age, genetic predisposition) and
modifiable (eg,
lifestyle, CVD risk factors) determinants, and
the direct as well as indirect effects of the selected treatment
management
plan. After adjuvant therapy, a proportion of
patients will experience an acute spontaneous recovery in CVRC49,50; a larger proportion, however, will sustain a marked, potentially irreversible,49 impairment in CVRC. As with healthy women, breast cancer survivors are ultimately subjected to the normal age-related increases
in risk factor burden and comorbidities that contribute to the established trajectory declines in CVRC.46
Unfortunately, those women experiencing irreversible CVRC impairments
during adjuvant therapy will lack the required CVRC
to withstand normal age-related pathologies. As a
result, the incidence of clinical overt dysfunction occurs at a much
earlier
age (Fig 1) than that observed in age-matched women without a history of breast cancer.
View larger version:
Fig 1.
Trajectory
decline in cardiovascular reserve capacity (CVRC) across the breast
cancer survivorship continuum. The postulated
trajectories of decline in CVRC in
patients with early-stage breast cancer (gold lines) compared with
age-matched decline
in women without a history of breast
cancer (blue line). Specifically, (A) at diagnosis, baseline CVRC is
determined by nonmodifiable
(age, genetic predisposition) and
modifiable risk factors (eg, hypertension, obesity, physical
inactivity). (B) After initiation
of adjuvant therapy, the extent and
magnitude of decline in CVRC is determined by the direct and indirect
effects of the selected
treatment management plan and its
interaction with modifiable and nonmodifiable risk factors. Several
trajectories of change
in CVRC, as assessed by left ventricular
ejection fraction and cardiorespiratory fitness, have been observed (C)
after completion
of adjuvant therapy: continued declines in
CVRC,28,49 spontaneous acute recovery,50 and plateau.51
Ultimately, however, similar to age-matched women without a history of
cancer, patients with breast cancer are subjected
to normal age-related and comorbid
pathologies. As CVRC depletes below a critical threshold, asymptomatic
maladaptation occurs,
which, without intervention, leads to
overt clinical dysfunction (eg, heart failure, myocardial infarction)
and ultimately
chronic morbidity and premature mortality.
Where to Go Next
If the tenets of the multiple-hit hypothesis are true, why is there not a greater extent of acute and long-term cardiovascular
toxicity in recent phase III trials51–53 and meta-analyses?54,55
Several potential explanations may explain this incongruence: one,
evaluation of subclinical cardiotoxicity or CVRC is seldom
studied or reported in the adjuvant setting;
two, most trials, with few exceptions, have limited cardiac follow-up
and variable
cardiac end point reporting; three, adjudication
of cause of death can be unreliable; four, few trials report even
10-year
outcomes; five, long-term outcomes are not yet
available for adjuvant trastuzumab or third-generation aromatase
inhibitor
trials; and six, data on the real-world
incidence of cardiovascular toxicity are limited in a nontrial context
and could be
expected to be higher given the preponderance to
exclude women with more unfavorable cardiovascular risk profiles.56
Clearly, many questions remain to be
addressed, and the clinical utility of CVRC in the oncology setting is
in its infancy.
Of relevance, the CCSS investigators recently
established the St Jude Lifetime Cohort, which will, among other things,
evaluate
physiologic mechanisms underlying
therapy-induced late effects in adult childhood cancer survivors using a
wide battery of
quantitative assessments together with
collection of patient-reported outcomes and tissue specimens.57
The establishment of similar cohort studies in adult patients with
breast and other cancers that include evaluation of CVRC
are urgently required to fully understand the
prevalence, magnitude, and pathophysiologic mechanisms of
therapy-induced late
cardiovascular effects. Such efforts, in
conjunction with existing tools used in the oncology setting, should
inform treatment
stratification, mortality-risk prediction, and
surveillance of therapy-induced toxicity/recovery across the cancer
survivorship
continuum. Furthermore, this information, in
turn, can guide the design and implementation of preventive and
early-intervention
strategies to abrogate or reverse impairments in
CVRC.
In conclusion, it is becoming
increasingly apparent that surviving early-stage breast cancer comes
with the risk of late-occurring
CVD. The importance of CVD is likely to further
increase with continual improvements in breast cancer–specific outcomes,
along
with the rapidly aging population. If current
trends continue, adjuvant therapy–associated CVD may hinder further
improvement
in overall survival after a diagnosis of early
breast cancer. The landscape of breast cancer prognosis and survivorship
has
and will continue to change dramatically over
the next two decades; with such changes, the central tenets and
implications
of CVRC are poised to become increasingly
important concepts in individualizing the curative-intent management and
long-term
surveillance of breast cancer and other adult
oncology populations.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the
disclosure declaration, the following author(s) indicated a financial or
other interest
that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a “U”
are those
for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description
of the disclosure categories, or for more
information about ASCO's conflict of interest policy, please refer to
the Author
Disclosure Declaration and the Disclosures of
Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: John R. Mackey, Roche, sanofi-aventis Research Funding: None Expert Testimony: None Other Remuneration: None
Acknowledgment
Supported in part by research Grants No. CA143254, CA142566, CA138634, CA133895, and CA164751 from the National Cancer Institute
and by George and Susan Beischer (L.W.J.).
No comments:
Post a Comment