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Focus on Performance Status

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David Alsadius1 M.D., Ph.D., Hanne Studsgaard Mikkelsen2, Mariusz Lukanowski2 M.D., Lars-Petter Strand3 B.Pharm
1 Eli Lilly Sweden AB, Gustav III:s Boulevard 42, P.O. Box 721. SE -169 27 Solna, Sweden
2 Eli Lilly Danmark A/S, Lyskær 3E, 2. tv. 2730 Herlev, Denmark
3 Eli Lilly Norge AS, Grenseveien 99, Postboks 6090, Etterstad, 0601 Oslo, Norway

David Alsadius, e-mail: alsadius_david@lilly.com

Since its introduction performance status has played a crucial role in clinical oncology research and practice and it continue to do so today. However, several issues regarding performance status remain to be fully addressed: How can we ascertain a reliable and reproducible assessment of performance status? Who should do the performance status evaluation – physicians, nurses, or the patients themselves – and when?

In 1948 it was suggested that four general criteria were the most important components to evaluate the usefulness of chemotherapeutic agents to control or cure cancer.1 These criteria included subjective improvement, objective improvement, length of remission and prolongation of life, and performance status (PS). This was the first time performance status had been discussed after the initial publication of what is now called the Karnofsky scale of Performance Status (KPS).2

The KPS was introduced by David A Karnofsky and colleagues to assess the PS of patients receiving nitrogen mustard chemotherapy for primary lung carcinoma. The patients were given a score on linear scale between 0 (dead) and 100 (normally active) summarizing their ability to perform daily activities, symptom burden and
what level of care or assistance they required (Table 1). After it was introduced, the KPS has been frequently used throughout oncology practice and research as a numerical tool to describe a patients’  general health.

In 1960, Charles G Zubrod and the Eastern Co-operative Oncology Group (ECOG) introduced a simpler scale in a study that compared the effect of nitrogen mustard and thio-TEPA for the treatment of breast cancer, lung cancer, Mb. Hodgkin, and melanoma.3 The ECOG PS scale assessed similar features as the KPS but with only five points ranging from 0 (normal activity) to 4 (unable to get out of bed). In 1982 this scale was modified to become the ECOG/ WHO scale and a performance score of 5 (Dead) was added (Table 1).4

Tabell 1
ECOG PSKPS
0Fully active, able to carry on all pre-disease performance without restriction100Normal, no complaints
1Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work90Able to carry on normal activities. Minor signs or
symptoms of disease
80Normal activity with effort
2Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours70Care for self. Unable to carry on normal activity or to do active work
60Requires occasional assistance, but able to care for most of his needs
3Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours50Requires considerable assistance and frequent medical care
40Disabled. Requires special care and assistance
4Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair30Severly disabled. Hospitalisation indicated though death nonimminent
20Very sick. Hospitalisation necessary. Active supportive treatment necessary
10Moribund
5Dead0Dead
Abbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; KPS, Karnovsky Performance Status
* Table 1. is an adaptation from Oken et al. Am J Clin Oncol 5:649-655, 1982.
Performance status in clinical trials

It has repeatedly been shown that PS is an important prognostic factor for survival in many of the major human cancer forms, e.g. breast cancer, colorectal cancer, and lung cancer.5 As a consequence, PS is regularly used in randomized clinical trials of cancer treatments as a stratification and selection variable.6 It is also used in clinical trials to evaluate patients’ responses to treatment. Also, time to PS deterioration is often assessed as one of the measures of an investigational products impact on quality of life.7 Although the KPS and the ECOG/ WHO scales are currently both being used in clinical oncology research and practice, the latter is often preferred due to its simplicity.

In current clinical trials most often patients with ECOG PS 0-1 are included, while patients with PS 2 or worse are usually excluded. Thus, the knowledge whether oncological treatment benefit extends to patients with PS 2 or worse is limited. In the lung cancer field retrospective analyses of prospective randomized studies that were conducted in the 1980s and 1990s have shown a poorer survival in patients with PS 2.8-9 In 1986 an ECOG trial of four different platinum combinations in NSCLC patients demonstrated impaired outcome for PS 2 patients compared to those with PS 0-1. PS 2 patients had a 10 percent incidence of treatment related deaths, which was substantially higher than the incidence in PS 0-1 patients. Consequently PS 2 patients were excluded from subsequent ECOG NSCLC trials.

This practice has extended to trials including other cancer diagnoses and often patients with PS 2 are excluded from the trials or they constitute a low proportion of the investigated patients.10 Although later analyses support the effect of chemotherapy in PS 2 or worse patients, some argue that considering the poor prognosis of these patients, patient-related end points other than survival e.g. symptom relief, clinical benefit, health-related quality of life (HRQoL) should play a central role in clinical trials of PS 2 patients.10-12 Indeed, a Norwegian phase 3 trial of NSCLC patients concluded that clinically meaningful improvements of symptoms and functioning can be achieved with chemo-therapy in PS 2 patients.13 The authors stated that chemotherapy to motivated PS 2 NSCLC patients should not be controversial from a HRQoL perspective.

There is still controversy to whether patients with poorer PS (ECOG PS ≥2) derive benefit from oncologic treatment, especially in a palliative setting.12 In a pooled analysis of nine pivotal trials of chemotherapy for metastatic colorectal cancer, Sargent et al. concluded that patients with ECOG PS 2 derive similar benefit from superior treatment as patients with PS 0 or 1 but with an increased risk of toxicity and 12 percent 60-day mortality.10 Sweeny et al. analyzed the outcome from the E1594 study, which compared cisplatin and paclitaxel with three newer chemotherapy doublets in advanced non-small cell lung cancer. They found that the 68 patients with ECOG PS 2 included in the study experienced a large number of adverse reactions, a short time to progression and an overall poor survival.14 However, further analysis showed that toxicity was only marginally worse and only two of five deaths in the PS 2 group could be attributed to treatment.

In many clinical treatment guidelines PS has an almost equal impact on treatment decisions equally as disease stage. Therefore appropriate assessment of PS is crucial for deciding the appropriate treatment plan and therapy goals e.g. whether to pursue a curative intent or palliative intent.

Performance status in the clinic

In the clinic, PS has been established as a tool to guide therapy decisions.9-12 It is used to aid the decision whether a patient is physically suitable and likely would benefit from oncological treatment or as a measure to assess the required intensity of palliative care. However, using PS to assess whether a patient will benefit from treatment has proven to be quite complicated.

It is reasonably fair to say that a worse PS is characterized by lower response rates to chemotherapy, shorter time to treatment failure and shorter progression free and overall survival. Despite this, there is evidence that oncological treatment of PS 2 patients can be of benefit when it comes to relieving symptoms and prolonging life. Patient selection is crucial and one needs to take into account the fact that the categories defined only by PS are inevitably heterogeneous. A PS 2 may be due to symptoms related to tumor burden (e.g. fatigue, pain, weight loss) but there can also be symptoms related to concomitant disease (e.g. cardiovascular disease, diabetes, osteoarthritis) or age related functional decline. For example, a 50-year old PS 2 patient confined to bed because of a single painful bone metastasis is very different from an elderly patient with few cancer-specific symptoms but confined to bed because of extensive cardiovascular co-morbidity.

The issue of reliability

Considering the impact PS status can have on both eventual enrollments in a clinical trial and on treatment decisions in the clinic, consistency in PS evaluation is of highest importance.

Accuracy and reliability of PS assessment need to be further evaluated and in many countries there is little formal training on
PS assessment for physicians and nurses.

Early studies of the interrater reliability of the KPS have shown discrepant results. In 1980s  Hutchinson et al. studied the interrater reliability of KPS between two physicians in an emergency room (ER) situation and with hemodialysis patients. The authors concluded that the KPS failed to meet the basic standards for clinical scales of reproducibility.15 Another study, where two sets of health care providers assessed advanced cancer patients showed that the KPS had a moderately high reliability.16 A study of cancer patients employing one set of physicians, primarily oncologists, and one set of mental health professionals as raters, showed that the KPS had a very good interrater reliability.6 The authors of this study argued that the reason that the Hutchinson study showed such poor results could be that the KPS is not applicable to non-cancer patients.

Sørensen et al. performed a study where three clinical oncologists with no specific PS training evaluated ECOG PS in 100 consecutive in-patients at a single center during the 3-month study period.17 They found that the agreement between observers was only moderate when all ECOG PS-groups were considered. However, agreement was higher in higher PS-groups and agreement on allocation of a patient to PS 0-2 versus PS 3-4 was high.

Do physicians, nurses and their patients agree?

A few studies have evaluated the agreement between PS ratings by physicians, nurses or patients and how these relate to prognosis. In a Japanese study of patients with NSCLC, Ando et al found that oncologists gave the healthiest PS assessments while nurses gave an intermediate assessment, and patients the poorest.18 They also found that oncologist-assessed PS best fitted the observed survival data and that patients themselves failed to distinguish survival of patients with performance status 1 and 2.

Between March 2000 and October 2001, Blagden et al. conducted a prospective, nonrandomized, double-blind, longitudinal study of PS in patients with NSCLC or SCLC conducted in the UK.19 They found a moderate agreement in PS rating between physicians and patients with an equally prognostic value in predicting survival. Although there was no sex difference in the patients’ assessment of PS scores, oncologists scored female patients more pessimistically than male. They concluded that it might benefit clinical practice to involve patients in PS assessment. This notion is also supported by a Canadian study on general oncology and palliative care patients.20

A Danish study presented at the 2013 ASCO Annual Meeting also concluded that it may be beneficial to involve patients in PS assessments.5 The authors analyzed a subset of 293 patients from larger prospective biomarker study, in which NSCLC patients themselves and the treating physician assessed PS at first visit. This study showed that oncologists and patients frequently disagree regarding PS and that the physicians often note a better PS score than the patients. Both patient and physician assessed PS were prognostic of survival. For a physician-assessed PS=0, a poorer patient PS did not predict a worse outcome. However for a physician-assessed PS=1 there was a non-statistically significant worse outcome if the patient PS was >1. These studies highlight the importance of determining on who is doing the PS evaluation in the clinic and for what purpose it is done.

Summary

PS is an important tool that helps guiding decisions that can have a substantial impact on the lives of cancer patients, their families and caregivers. Considering its importance, it is crucial that PS assessment in clinical practice and research is consistent and reliable. In the future more research is needed to answer the question on how and by whom PS is best assessed. The ambiguity of poor PS needs to be addressed and studies undertaken to explore the value of treatments in these patients, where outcomes other than survival can play a crucial role. Current treatment development has increased the number and diversity of therapeutic options that can be proposed to patients in cancer areas where little or no progress had been achieved for decades.
For these patients, who are often diagnosed in advanced stages, PS assessment for selection both in clinical research and practice remains a crucial challenge.

References

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  2. Karnofsky DA, Abelman WH, Craver LF, Burchenal JH. The use of nitrogen mustard in the palliative treatment of carcinoma. Cancer 1948; 1: 634-656.
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