Cardiopulmonary exercise testing for the selection of patients undergoing surgery for lung cancer: Friend or foe?

Full text

Cardiopulmonary exercise
testing for the selection of
patients undergoing surgery for
lung cancer: friend or foe?
Eric Lim,
1
Michael Beckles,
2
Chris Warburton,
3
David Baldwin
4
The contribution of exercise testing for
risk assessment for lung resection is well
established and has been embedded in
international guidelines from Europe
1
and
the USA.
2
There are many forms of exer-
cise tests (6 min walk, 12 min walk,
shuttle walk, stair climbing), but the most
established investigation is formal assess-
ment of maximum oxygen consumption
during exercise (VO
2
max). British and
American (American College of Chest
Physicians (ACCP)) guidelines use VO
2
max as the ultimate assessment of opera-
tive risk, positioned at or near the end of
the functional algorithm,
3
whereas Euro-
pean guidelines recommend the use of this
test much earlier in patients with a forced
expiratory volume in 1 s (FEV
1
) or carbon
monoxide transfer factor (TlCO)<80%
predicted.
12
Numerous cohort studies and a meta-
analysis report the association of low VO
2
max and ‘high risk’lung resection.
4e18
However ‘high’is not quantified and
‘risk’is not defined, two fundamentally
important definitions if guidelines that
use these terms are to be applied clini-
cally. Here we focus on validity of the
VO
2
max studies and the clinical utility of
the available evidence with respect to
individual interpretation of risk.
SAMPLE SIZE AND PRECISION OF RISK
ESTIMATION OF DEATH
Arguably, the most important outcome
when considering surgery for lung cancer
is the ability to survive the procedure.
Themostapparentlimitationofthe
currently available evidence is the lack of
appropriately powered studies to address
this.Theprecisionofariskmodelisnot
specifically dependent on sample size,
but rather the number of eventsdthat
is deathsdan uncommon outcome in
thoracic surgery. In the UK, lobectomy,
the most common procedure for lung
cancer, carried an operative mortality of
w2% in 2004e2005,
19
and in the USA the
mortality rate has been reported to range
from 2.3% to 4.1%.
20
Reflective of this,
the largest study in this context on VO
2
max(422patients)hadonly15deaths.
What is clearly more disconcerting is that
publications for which recommendations
on estimation of operative mortality risk
have been based have sample sizes
ranging from 8 to 160.
21
UPPER LIMITS OF UNCERTAINTY FOR
SAFE CUT-OFF VALUES
Many studies have defined arbitrary cut-off
values ranging from 15 to 20/ml/kg/min as
a‘safe’cut-off value
412e14
because above
these levels no patient experienced an
adverse event. What is the validity of this
type of recommendation?
The answer lies in the uncertainly that
surrounds the observation of no events (ie,
upper 95% CI), a function of the sample
size. For a standard binomial distribution,
the upper limit of the CI of zero events
with the sample size of 8e160 corre-
sponds to 42e2.7%, respectively (figure 1),
illustrating high limits of uncertainty in
the majority of studies with smaller
sample sizes.
ALTERNATIVE MODELS FOR RISK
ESTIMATION OF DEATH
Given these limitations, are there any
other alternatives for the risk assessment
for operative morality?Thoracoscore is
a composite scoxring system that can be
used to quantify risk. It is a logistic
regression-derived model with coefficients
provided for individual risk factors, calcu-
lated to provide a percentage probability
of death. It is currently the best model and
was developed from a sample size of
15 183 patients with 338 deaths, and
provides excellent discrimination with an
area under the curve of 0.82.
22
Further-
more, it has been validated in different
populations.
23
Apart from superior statis-
tical power, much larger sample size,
external validity and excellent perfor-
mance, the logistic risk model carries two
further attractive advantages compared
with VO
2
max assessment: it is cost free
and can be universally available.
OTHER OUTCOMES AND COMPOSITE END
POINTS
The consistent message that lower values
of Vo
2
max are associated with higher risk
of complications is to be expected as
a measure of cardiovascular fitness. From
a patient’s and clinician’s perspective,
however, the nature of the complications is
of central importance. All studies to date
have used composite end points and, when
multiple outcomes are combined, it
becomes difficult to interpret the impact of
each individual component. It has been
recommended that each outcome should
have a similar weighting or clinical impor-
tance to facilitate clinical interpretation.
24
For example, death and myocardial infarc-
tion would be combined to estimate the
total number of patients that may have
experienced a myocardial infarction and
survived, added to those that have
(presumably) experienced a myocardial
infarction and died.
Researchers, however, may use
composite outcomes to increase the power
of the study (by increasing event rate)
and therefore increasing the chances of
achieving statistically significant results.
25
The corollary is that important outcomes
such as death can be piggybacked within
the pool of less important outcomes such
as atelectasis
57e911e14 16
or purulent
sputum,
4
giving rise to considerable diffi-
culties for the clinician and, more impor-
tantly, the patient to evaluate the
importance of the overall result. We
believe that most patients would not
consider readmission to the intensive
care unit,
11
atelectasis,
57e911e14 16
arrhythmia
46e8101314
or postoperative
CO
2
retention
68e10 13 16
as ‘prohibitive’
complications leading them to refuse
surgery.
1
Imperial College and Academic Division of Thoracic
Surgery, The Royal Brompton Hospital, London, UK;
2
Department of Acute Medicine, The Royal Free
Hospital, London, UK;
3
Department of Respiratory
Medicine, Aintree Chest Centre, Liverpool, UK;
4
Respiratory Medicine Unit, David Evans Research
Centre, Nottingham University Hospitals, Nottingham,
UK
Correspondence to Eric Lim, Academic Division of
Thoracic Surgery, Royal Brompton Hospital, Sydney
Street, London SW3 6NP, UK; e.lim@rbht.nhs.uk
Thorax October 2010 Vol 65 No 10 847
Editorial
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QUANTIFICATION AND INTERPRETATION
OF RISK
A clear explanation of risks and benefits is
central to good consenting practice when
offering treatment options to our
patients. Dichotomous categorisation of
‘high’and ‘standard’risk using VO
2
max
for risk assessment, accompanied by
a combination of varied outcomes (some
of which have little influence on patient
decision making) renders the information
difficult to apply in practice. The lack of
a numerical estimate leads to subjective
interpretation of ‘high’;moreover,many
studies do not document the uncertainty
(confidence limits) that surround their
estimates. As there is no accepted level
of baseline risk, it is not possible to
quantify the relative magnitude of ‘high’
to facilitate the interpretation.
COST OF GETTING IT WRONG
It is intuitive that clinicians seek to protect
the interests of their patients, and some
may wonder if a discussion of the quanti-
fication and interpretation of risk is rele-
vant as opposed to acceptance and
avoidance of risk based on published values.
In the CALGB 9238 study, the largest in the
series (with 422 patients), physicians were
allowed to offer surgical treatment of
patients with ‘very high risk’,defined as
FEV
1
<900 ml and VO
2
max of <15/ml/kg/
min. Of the 68 patients in the ‘very high
risk’group, there was only one post-
operative death within 30 days and a total
of three in-hospital deaths.
17
More impor-
tantly, on follow-up, the operated patients
in the very high risk group had more than
double the median survival compared with
the non-operated patients (36.0 months vs
15.8 months, p<0.001), illustrating accept-
able procedural mortality and morbidity
with twice the median survival with case
selection on parameters independent of VO
2
max. Denying patients with ‘prohibitive’
values of VO
2
max the opportunity to
consider surgery as a management option
may in fact be against their best interests.
As the study was not randomised, it is
important to bear in mind the invariable
presence of selection bias, and the possi-
bility that a better result was achieved by
offering surgery to fitter patients with less
co-morbidity. Our point is more to ques-
tion the ‘conventional’lower limit of safety
and the results that can be achieved by
further selection.
THE FUTURE
We acknowledge the consistent message
that low levels of VO
2
max are associated
with increased complications from surgery.
However, we believe current recommen-
dations are flawed by small sample sizes,
resulting in imprecise risk estimates.
Moreover, the lack of numerical quantifi-
cation leads to difficulties in defining the
level of acceptable risk. Furthermore, the
use of composite outcomes leads to a lack of
agreement on the importance of the risks,
and the incongruence limits the clinical
applicability to inform patients on the
decision to undergo surgery. We believe that
management options should be discussed
at a multidisciplinary level but decisions
should be undertaken at patient level. This
is because patients are heterogeneous, with
individual perceptions on the value of
benefit and risk. As the lower limits of
safety remain imprecisely defined, patients
with multidisciplinary team-defined
‘prohibitive’levels of risk may not be
offered the opportunity to consider surgery
as an option and denied the possibility of
increased life expectancy.
There may also be a degree of concern if
postoperative quality of life may be a trade-
offforanyincreaseinlifeexpectancyinthe
high risk cohort; however, prospective
studies indicated that patients traditionally
considered at higher risk of lung resection
had postoperative physical and emotional
quality of life scores similar to those
observed in younger and fitter patients.
26
Before widespread use, further work
needs to be performed to determine if
cardiopulmonary exercise testing is an
independent predictor of mortality (eg,
above and beyond that of Thorascore), to
relate the study to individual outcomes that
would influence the decision to undergo
surgery, to provide numerical quantification
of risk with an estimate of uncertainty and
to demonstrate validity in different cohorts.
Competing interests None.
Provenance and peer review Commissioned;
externally peer reviewed.
Published Online First 13 July 2010
Thorax 2010;65:847e849.
doi:10.1136/thx.2009.133181
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Pseudomonas aeruginosa
infection in cystic fibrosis:
prevent, eradicate or both?
Ernst Eber, Maximilian S Zach
Lung disease in cystic fibrosis (CF) starts
early in life. Infection, inflammation,
reduced lung function and abnormal chest
CT findings are present in a significant
proportion of infants with CF at a time
when many of these children have no clini-
cally apparent lung disease.
1e6
Infection and
inflammation are intimately linked early in
the course of CF lung disease.
27e9
The
detection of airway inflammation in the
absence of apparent infection led to the
speculation that CF is associated with an
intrinsic abnormality of immune regula-
tion.
10
However, more recent data argue
against a primary CF-associated dysregula-
tion of local immune function where
inflammation might precede infection; they
rather support the central role of bacterial
pathogens in initiating and sustaining the
neutrophil-mediated airway inflammation
characteristic of CF lung disease, with
ahigherinflammatory burden in children
infected with Pseudomonas aeruginosa (PA)
than in those infected with organisms other
than PA or uninfected.
61112
Chronic respi-
ratory infection is one of the main charac-
teristics of CF and significantly contributes
to morbidity and mortality.
12 13
In young
children Staphylococcus aureus,Haemophilus
influenzae and PA are the major lower airway
pathogens.
12 13
Chronic infection with PA is
known to be associated with a worse prog-
nosis in children, adolescents and adults,and
patients with mucoid PA strains do worse
than those with non-mucoid strains.
14e18
Thus, prevention or early detection and
treatment of infection, in particular with
PA, may prevent or delay irreversible lung
damage from inflammation and conse-
quently may improve prognosis. In order to
prevent acquisition of PA, hygienic measures
to decontaminate environmental reservoirs
of this organism including medical equip-
ment have been stressed, and CF centres
have adopted meticulous microbiological
surveillance and effective segregation poli-
cies to limit cross-infection between
patients. Furthermore, several trials have
been undertaken to assess the value of
vaccination as a preventive strategy for PA
infection but, with the variable outcomes of
these trials, vaccines against PA cannot be
recommended.
19
At present, early treatmen t
of initial infectiondthat is, an attempt to
eradicate PAdis the agreed standard.
20
Literature on antibiotic prophylaxis of PA
infection has so far remained scarce.
21 22
In this issue of Thorax, Tramper-
Stranders et al report on a randomised
controlled trial investigating the effec-
tiveness of cycled antibiotic prophylaxis in
children with CF (see page 915).
23
Chil-
dren between 0 and 18 years of age
received 3-monthly 3-week treatments
with oral ciprofloxacin and inhaled
colistin or placebo for 3 years. The authors
apparently chose this regimen because
many CF centres across Europe have used
the combination of oral ciprofloxacin and
inhaled colistin as eradication therapy for
PA, going back to the first randomised
controlled trial of an eradication regimen
almost 20 years ago.
24
Patients were
followed at 3-monthly intervals in
between treatment cycles and respiratory
specimens collected for microbiology
studies were either oropharyngeal cough
swabs or sputum samples (notably, the
vast majority of patients did not produce
sputum). In addition, serum samples were
collected every 6 months for measurement
of anti-Pseudomonas antibodies. Infection
with PA (the primary end point) was
defined as either two positive cultures
taken >1 week apart or one positive
culture and a ‘severe pulmonary exacer-
bation’. Nineteen out of 65 patients (29%)
reached the primary end point (in only 4
of them was PA detected in sputum);
information on how many strains were
mucoid or non-mucoid is not given.
Fourteen patients had positive antibody
titres during the study period once or
more often; 10 of them were culture-
positive before they were serology-posi-
tive. This study once more shows that
detection of infection in children with CF
is difficult. In general, young children are
not able to expectorate sputum, and
oropharyngeal cultures do not reliably
predict the presence of bacterial pathogens
in the lower airways of young children
with CF.
13 25
Thus, cultures from bron-
choalveolar lavage (BAL) fluid are usually
taken as the gold standard for detection of
infection in the lower airways. However,
owing to sampling problems, even a nega-
tive BAL fluid culture or the absence of
a particular organism on culture does not
guarantee that the organism is not present
in the lungs of the patient.
26
For this
reason, additional markers of infection are
desirable and the use of specific serum
antibodies against PA may be helpful in
defining the status of PA infection.
However, the majority of patients are
antibody-negative at the time of first
infection so specific antibodies against PA
alone are not recommended to diagnose
early infection.
27
With oropharyngeal
cough swabs being the prevailing respira-
tory specimens, one might speculate that at
least some patients with positive upper
airway cultures might have had negative
Klinische Abteilung fu
¨r Pulmonologie und Allergologie,
Univ-Klinik fu
¨r Kinder- und Jugendheilkunde,
Medizinische Universita
¨t Graz, Graz, Austria
Correspondence to Dr Ernst Eber, Klinische Abteilung
fu
¨r Pulmonologie und Allergologie, Univ-Klinik fu
¨r Kinder-
und Jugendheilkunde, Medizinische Universita
¨t Graz,
Auenbruggerplatz 34, 8036 Graz, Austria;
ernst.eber@medunigraz.at
Thorax October 2010 Vol 65 No 10 849
Editorial
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lung cancer: friend or foe?
selection of patients undergoing surgery for
Cardiopulmonary exercise testing for the
Eric Lim, Michael Beckles, Chris Warburton and David Baldwin
doi: 10.1136/thx.2009.133181
2010 65: 847-849 originally published online July 13, 2010Thorax
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