Performance Status (Functional Status)
Performance Status (PS) is one dimension of Quality of Life which health professions
and patients recognize as something that is important to try and maintain or improve.
Definition
Performance Status is an attempt to measure the functional status of the patient at a given
time. As such it is but one facet of the patient’s overall well-being, which includes
physical, psychological, emotional, spiritual and social aspects, as influenced by their
experiences, beliefs and perceptions.1
Performance Status was introduced in the middle of the 20th century as a way of
predicting a patient’s survival.2 Scales for expressing the level of function are named
after their originators, Karnofsky3,4 (1948, 1949) and Zubrod (1960)5. The latter is the
simpler of these, but has a number of alternative names including ECOG (Eastern
Cooperative Oncology Group) and WHO (World Health Organization) . However it is
important to be aware of both, since both are widely used in the medical literature (see
Appendix: Performance Status Definitions). They are not directly comparable, since they
measure different aspects of function. For purposes of simplicity the Zubrod scale is
discussed here, in which represents 0 represents no restriction of function and 5
represents death. Therefore the higher the Zubrod score, the more restricted the patient is
with greater disability.
There are a number of problems associated with the use of these scales. There is interobserver variability (disagreement between two people estimating the status at the same
time)6, they are subjective7 (rely on patients’ description of their activities) and cannot be
verified. Physicians, nurses and the patients themselves disagree on the estimate of
performance status8. Status does not fall into neat categories but is a continuum. On a
scale of 0-5, there may be more similarity between two patients with scores of 3 and 4,
than between two patients with a score of 3, if the first pair are very close to the cut off
point between 3 and 4, and the second pair are close to the cutoff points between 2 and 3,
and 3 and 4 respectively.
Despite these problems the scales continue to show good correlation with survival in
population studies. Indeed this is intuitive. For instance a scale from 0-5, in which 0 is
normal health and 5 is dead is almost guarantied to be correlated with subsequent
survival. This does not, however mean that it has good predictive value (predicting the
outcome of an individual patient to a specific intervention).
Prognostic factors vs. Benefit
A prognostic factor is something that is statistically associated with a particular
outcome9. For instance it might be determined that women have a worse survival than
men for a particular cancer. In which case, gender would be considered a prognostic
factor which might assist in predicting survival. This has nothing to do with benefit.
Benefit is the change that occurs from a baseline value when an intervention is applied to
a particular patient population. For instance when the above women receive a certain
drug, 30% of them may experience relief of pain and 45% experience improvement in
their breathing. These patients can be considered to have derived a clinical benefit. The
life span of a group of women who receive a particular drug may be longer than a control
group who receive only pain medication. These women may be said to have derived a
survival benefit. As with prognostic factors, benefit must be defined in relation to a
specific outcome of interest.
The real issue is whether performance status can reliably predict who will benefit or not
from an intervention. Commentators have often confused survival with benefit. One of
the problems in providing reliable data is that although we do not know exactly what
percentages of patients will fall into each of the categories of PS 0-4, most of the research
on chemotherapy has been done with patients who were classified as having performance
status 0-2, suggesting that these categories are more common. Nevertheless there is now
a growing body of evidence of the experience and benefit in patients with performance
status 3-4.
It is incorrect to consider that performance status is a critical element in determining
whether or not patients will tolerate chemotherapy, since this is not supported by the
medical literature. It would be more correct to state that the higher the ECOG
performance status, in general, the worse the outcome with or without treatment. Indeed,
sometimes tolerance is even inversely related to performance status,10 that is patients with
a higher ECOG have less problems, and also have the potential to improve more in terms
of symptom control (for instance, see below: Lung Cancer). Nor is there evidence that
performance status should guide chemotherapy dosing.
Lung Cancer
Discussions around performance status in lung cancer usually distinguish between nonsmall-cell and small cell lung cancer because of the better response to chemotherapy of
the latter group.
Non-small cell lung cancer
In particular reference is made to a well publicized study of four different types of
chemotherapy, in which the inclusion of patients with a performance status of 2 was
discontinued because of preliminary concerns about toxicity11.
However further research found that these preliminary findings were incorrect12, and that
the problems observed were actually due to the patients’ disease not their treatment.
Another study demonstrated a survival benefit in this group13. A recent review of this
issue14 concluded that in fact these patients did benefit from chemotherapy when clinical
benefit was considered as an outcome. In fact it has been pointed out several times15,16
that it is precisely those patients whose disease status has reduced their performance
status, who have the most to gain from chemotherapy where the primary purpose is to
relieve symptoms. In the Cancer Research Campaign trials it was patients with a PS 2
who experienced the greatest improvement in quality of life during the first six weeks. In
a review of the experience of a large London cancer hospital, Hickish specifically
identified patients with a performance status of 3, and demonstrated that ‘the majoritya of
patients with the worst prognosis have symptom relief from chemotherapy’17.
However it was incorrect and incomplete interpretation of preliminary data such as that
described above that has led to a belief by some people that patients with impaired PS are
at higher risk from toxicity, whereas their poorer outcome is actually due to their disease.
Symptomatic improvement has been demonstrated to be highly valued by patients18,
often more than any survival benefit, and is therefore a critical element in any discussion
with patients about options.
Symptomatic improvement is consistently observed at a two to three-fold greater rate
than the objective tumour response rate. 19
An earlier review (meta-analysis)20 of all trials of chemotherapy compared to supportive
care alone had included all performance status groups (0-4) and had shown no difference
in the beneficial effect of chemotherapy between these different groups. As Lilenbaum
states:
“…patients who present with an aggressive course manifested by rapidly
progressive symptoms and worsening PS should be considered candidates for
equally aggressive treatment…the benefit in absolute numbers…is still
significantly superior to the outcome associated with no treatment at all…the
rationale for excluding patients with a PS of 2 from clinical research and from the
potential benefits of chemotherapy has been vigorously challenged and is no
longer valid”.
Baka and colleagues selected patients with PS as low as KPS 30-40 (severely disabled,
hospitalization imminent)b, and up to 80 and found an objective response rate of 8% and
a further 16% achieving disease stabilization, but a significant improvement in both
patient reported symptoms and PS. For instance average KPS increased from 60 to 85 by
the 6th cycle of chemotherapy.19
Consequently a recent large trial designed to investigate the potential benefits of
chemotherapy in this disease (compared to supportive care alone) allowed any patient to
enter, regardless of performance status, showed no lack of benefit (survival) in any
subgroup, and all groups of patients showed subjective improvement or maintenance of
quality of life compared to supportive care21. Contrary to what has often been stated, the
beneficial palliative effects outweighed the adverse side effects of the chemotherapy.
As Silvestri22 comments, when patients are presented with choices, their preferences
frequently clash with those of their oncologists, are fixed (do not change in retrospect
a
b
54%
Equivalent to Zubrod 3
after experiencing chemotherapy) and unpredictable (because they are unique to the
individual’s personal experiences and values)23 but logical;
“The decision for treatment should reside with the patient with input from his or
her physician…either way, the decision will have been the right one for them”.
Small cell lung cancer
Less attention is paid to PS in this variety of cancer because of the overall better results
achieved with chemotherapy. However controversies have existed regarding the benefit
of chemotherapy for people whose initial treatment failed and have poor performance
status.
A recent study comparing chemotherapy with supportive care in this group demonstrated
the superiority of chemotherapy and that if anything, the poor PS patients benefited most.
Other Cancers
It is often stated that there is literature demonstrating that most people with a
performance status of 3 or 4 derive no benefit from chemotherapy’. This is not true, and
is usually not accompanied by any specific literature to justify the statement. On the other
hand the statement that in most circumstances in solid tumours performance status is the
single most important prognostic factor is largely true. The confusion arises in failing to
state what a ‘prognostic factor’ actually is, and in failing to separate this from the concept
of ‘benefit’, as already discussed. Other versions of this are sometimes stated as saying
that you don’t need a guideline, that everybody knows that in solid tumour oncology that
if the patient has a performance status of 3, that unless you have lymphoma, testicular
cancer, or small cell lung cancer, you do not benefit from chemotherapy, and that has
been shown in trial after trial in multiple disease sites.
Such comments demonstrate a lack of familiarity by some oncoplogists with what is
known about performance status and benefit, and are not based on any scientific data.
There is a misconception that small-cell lung cancer patients are a unique class in terms
of deriving benefit and those with extensive stage disease have lower response rates and
survival than colorectal cancer patients’
This oft repeated dogma is addressed by Bowcock and colleagues, stating that24
‘It is therefore easy to assume that patients presenting at an advanced stage with a
poor performance status secondary to high tumour burden would gain little
benefit from chemotherapy’
Bowcock uses the term ‘poor’ to refer to performance status of 3 and 4, and ‘moribund’
to refer to a performance status of 4 alone. They describe their experience with moribund
patients who gained valuable quality time. They argue, as have others25, that due to the
ability of chemotherapy to reverse negative metabolic effects of the cancer, it is possible
to produce improvement in even ‘the catastrophic physiological state of terminal cancer,
even in seemingly hopeless cases’. They state that this is ‘well recognized among
oncologists’.
As in lung cancer, it is not uncommon for patients with the worst function to benefit
most, since they have the most to gain. In an analysis of over 3,000 patients treated in 19
trials of advanced colorectal cancer, with 5-fluorouracil, the most commonly used drug in
this disease26, it was patients with a PS of 2 or greater who showed the most benefit when
the treatment was intensified by the addition of leucovorin.
The confusion that appears to exist in some people’s minds around this topic is again
demonstrated in this study by the fact that on the one hand it is true that the group of
patients with a higher ECOG number or poorer PS had a lower probability of their
tumour objectively responding to chemotherapy (generally they had larger tumours), and
did not live as long. That is, their PS was a prognostic factor. However when the effect of
adding the second drug (leucovorin) was examined the patients who had the biggest
improvement in both of these outcomes were those with a PS of 2 or greater. Again this
illustrates the difference between the concepts of a prognostic factor and benefit. It is
benefit which must play an important part in the actual decision making between
physician and patient. Obviously, as stated by Baka and colleagues,19 in patients with
more impaired function and hence a worse prognosis for survival, the relative emphasis
on palliation of symptoms and quality of life versus survival will be weighted to the
former goals.
Similarly Archer and colleagues27 refer to ‘entrenched scepticism’ due to mistaken
beliefs about the toxicity of chemotherapy, of patient preferences and their willingness to
endure side effects in order to obtain relief from the symptoms of their disease. In
considering the use of chemotherapy in patients with higher performance status scores, it
is important to realize that dying patients wish to retain control for as long as
possible,28,29 and that intervention that buys them some time may be what is necessary to
achieve that end for them and their families. Misconceptions arise because oncologists
appear to over estimate the side effects of cancer therapy and underestimate benefit
compared to their patients as discussed in Clinical Judgement: Decision making in
oncology: Preferences and values. 30 Again, it is often stated that poor performance status
is associated with unacceptable toxicity. In one of the largest series (1,219 patients) on
the toxicity of fluorouracil10 while patients with performance status 2 or greater showed
more haematological toxicity, with regards to the non-haematological toxicity which is
what matters to patients, this was less in the group with a performance status of 2+ than
those with a status of 0 or 1.
1
Testa M, Simonson D. Assessment of quality-of-life outcomes. NEJM 334(13): 835-840, 1996
Sǿrensen J, Klee M, Palshof T et al. Performance status assessment in cancer patients. An inter-observervariability study. Br J Can 67: 773-775
3
Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer, in Macleod
CM (ed): Evaluation of Chemotherapeutic Agents. New York, Columbia University Press, 1949. p. 199205
4
Karnofsky D, Ableman W, Craver W, et al. The use of nitrogen mustard in the palliative treatment of of
carcinoma. Cancer 1: 634-656
5
Zubrod C, Scheiderman M, Frei E, et al. Cancer-appraisal of methods for the study of chemotherapy of
cancer in man: thiophosphamide J Chronic Dis 11: 7-33, 1960
6
Taylor AE, Olver IN, Sivanthan T, Chi M, Purnell C. Observer error in grading performance status in
cancer patients. Support Care Cancer. 1999 Sep;7(5):332-5
7
Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and
guidelines. J Clin Oncol. 1984 Mar;2(3):187-93.
8
Ando M, Ando Y, Hasegawa Y, Shimokata K, Minami H, Wakai K, Ohno Y, Sakai S. Prognostic value of
performance status assessed by patients themselves, nurses, and oncologists in advanced non-small cell
lung cancer. Br J Cancer. 2001 Nov 30;85(11):1634-9.
9
Levine MN, Browman GP, Gent M, Roberts R, Goodyear M: When is a prognostic factor useful?: a guide
for the perplexed. J Clin Oncol 9: 348-356. 1991
10
Meta-Analysis Group In Cancer. Toxicity of fluorouracil in patients with advanced colorectal cancer:
effect of administration schedule and prognostic factors. J Clin Oncol. 1998 Nov;16(11):3537-41.
11
Schiller J, Harrington D, Belani C, et al. Comparison of Four Chemotherapy Regimens for Advanced
Non-Small-Cell Lung Cancer N Engl J Med 2002 346: 92-98
12
Sweeney CJ, Zhu J, Sandler AB, Schiller J, Belani CP, Langer C, Krook J, Harrington D, Johnson DH
Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594:
a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer. 2001 Nov
15;92(10):2639-47.
13
Lilenbaum R, Herndon J, List M et al. Single-agent versus combination chemotherapy in advanced nonsmall lung cancer: a CALGB randomized trial of efficacy, quality of life, and cost-effectiveness. Proc
ASCO 21: #2, 2002
14
Lilenbaum R Management of advanced non-small-cell lung cancer in patients with a performance status
of 2. Clin Lung Cancer. 2004 Jan;5(4):209-13.
15
Lilenbaum op cit
16
Billingham LJ, Cullen MH: The benefits of chemotherapy in patient subgroups with unresectable nonsmall-cell lung cancer. Ann Oncol. 2001 Dec;12(12):1671-5
17
Hickish TF, Smith IE, O'Brien ME, Ashley S, Middleton G: Clinical benefit from palliative
chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors.
Br J Cancer. 1998 Jul;78(1):28-33
18
Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patients with advanced non-small
cell lung cancer: descriptive study based on scripted interviews. BMJ. 1998 Sep 19;317(7161):771-5
19
Baka S, Ashcroft L, Anderson H, Lind M, Burt P, Stout R, Dowd I, Smith D, Lorigan P, Thatcher N.
Randomised phase II study of two gemcitabine schedules for patients with impaired performance status
(Karnofsky performance status  70) and advanced non-small-cell lung cancer. J Clin Oncol 23(10) 2005
10.1200/JCO.2005.01.003
20
Non-small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: a metaanalysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung
Cancer Collaborative Group. BMJ. 1995 Oct 7;311(7010):899-909.
21
Spiro SG, Rudd RM, Souhami RL, Brown J, Fairlamb DJ, Gower NH, Maslove L, Milroy R, Napp V,
Parmar MK, Peake MD, Stephens RJ, Thorpe H, Waller DA, West P; Big Lung Trial participants.
Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without
detriment to quality of life. Thorax. 2004 Oct;59(10):828-36
22
Silvestri G. Chemotherapy for advanced lung cancer: is the glass half full or half empty? Thorax. 2004
Oct;59(10):821.
2
23
Brundage MD, Feldman-Stewart D, Cosby R, Gregg R, Dixon P, Youssef Y, Mackillop WJ. Cancer
patients' attitudes toward treatment options for advanced non-small cell lung cancer: implications for
patient education and decision support. Patient Educ Couns. 2001 Nov;45(2):149-57
24
Bowcock SJ, Shee CD, Rassam SM, Harper PG. Chemotherapy for cancer patients who present late.
BMJ. 2004 Jun 12;328(7453):1430-2.
25
Luigi Cavanna, Antonio Lazzaro, Raffaella Bertè, Livia Bidin, Giuseppe Civardi, Carlo Moroni,
Mariangela Palladino, Carmelina Rodino', Daniele Vallisa. Oncologic emergencies secondary to advanced
colorectal cancer (ACC) successfully treated with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX 4).
Report of three cases. Proc ASCO 2002, #2385.
26
Meta-analysis Group in Cancer: Modulation of fluorouracil by leucovorin in patients with advanced
colorectal cancer: an updated meta-analysis. J Clin Oncol 22: 3766-3775, 2004
27
Archer VR, Billingham LJ, Cullen MH. Palliative chemotherapy: no longer a contradiction in terms.
Oncologist. 1999;4(6):470-7.
28
Smith R. A good death. An important aim for health services and for us all. BMJ. 2000 Jan
15;320(7228):129-30.
29
Debate of the Age Health and Care Study Group. The future of health and care of older people: the best
is yet to come. London, Age Concern 1999.
30
Goodyear M. Clinical Judgement: Medical Decision Making in Oncology. 2006
http://myweb.dal.ca/mgoodyea/files/clinicaljudgement.doc