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The prognostic value of WHO performance status in relation to quality of life in advanced colorectal cancer patients

 European Journal of Cancer, Volume 66, October 2016, Pages 138 - 143

Abstract

Introduction

Performance status (PS) is an established prognostic factor in patients with advanced cancer and is usually scored by the treating physician. The EORTC QLQ-C30 questionnaire as reported by cancer patients is a validated tool to assess quality of life (QoL). Subjectivity plays a role in both assessments, and data on a direct comparison are scarce.

Methods

We compared the prognostic value for overall survival (OS) of the WHO PS to the baseline physical function scale of the EORTC QLQ-C30 (QLQ-C30 PF) in a prospective randomised phase 3 trial in advanced colorectal cancer (ACC), the CAIRO study. Patients were divided into two groups based on the baseline QLQ-C30 PF. QLQ-C30 PF was considered ‘good’ if the score was more than 66.7% and ‘poor’ if 66.7% or less. Results were validated in a subsequent phase 3 study in ACC, the CAIRO2 study.

Results

The median OS for patients with a ‘good’ QLQ-C30 PF and a ‘poor’ PF in patients with WHO PS 0 was 20.3 months (n = 300) and 10.4 months (n = 44), in patients with WHO PS 1 16.8 months (n = 125) and 10.1 months (n = 63), and in patients with WHO PS 2 16.2 months (n = 11) and 9.9 months (n = 12), respectively. In a Cox regression model which included other prognostic factors, ‘good’ versus ‘poor’ QLQ-C30 PF was significantly prognostic for OS (0.57 95% confidence interval: 0.46–0.72), but not WHO PS. These results were confirmed in the CAIRO2 study.

Conclusions

We demonstrate in ACC patients that PF, as assessed by patients using the EORTC QLQ-C30, is superior in terms of prognostic value to WHO PS as scored by physicians. Our data support to include the results of baseline EORTC QLQ-C30 PF instead of WHO PS as a stratification parameter in oncology trials.

Highlights

  • Physical functioning as assessed by patients is more prognostic than performance status as assessed by physicians.
  • Baseline physical functioning of the EORTC QLQ-C30 should be included as a stratification parameter in clinical trials.

Keywords: WHO performance status, Quality of life, Colorectal cancer, Physical functioning.

1. Introduction

Assessment of the performance status (PS) is an important tool for physicians to evaluate physical functioning of patients. In clinical oncology, it is widely used to decide which patients are physically suitable for treatment. It is an established prognostic factor for survival [1] and therefore frequently used as a stratification parameter in randomised clinical trials. Various scoring systems of PS are used: Karnofsky introduced the first performance score in 1948 [2]. In 1960, the Eastern Co-operative Oncology Group (ECOG) PS scale was introduced [3], which is more simple and has a better predictive validity [4]. This was later adapted to a scale of 6 points, which is currently known as the ECOG PS or WHO PS score. Obviously, subjective factors may play a role in the assessment of the PS of the patient by the physician, and the quality of this assessment may vary [1].

The current standard of patient-centred care has resulted in more attention to patient-reported outcomes (PROs). These PROs are increasingly considered as important measures to assess the effects of treatment in terms of toxicity and well-being as compared to outcome as assessed by physicians [5]. The prognostic value of PROs has recently been studied in several tumour types [6], [7], and [8]. The quality of life (QoL) questionnaire (QLQ) C30 of the EORTC is one of the most frequently used questionnaires to assess PRO in oncology clinical trials. The QLQ-C30 is divided in global health status/QoL, functional scales and symptom scales items.

A cross-validation of the Karnofsky PS and the QLQ-C30 [9] showed that Karnofsky PS only reflects physical functioning, whereas the QLQ-C30 reflects a greater scope of physical functioning by also including the symptoms of pain, breathing and fatigue as well as non-physical functioning concerning social, emotional, and cognitive well-being. In the phase 3 CAIRO study of the Dutch Colorectal Cancer Group [10] in patients with advanced colorectal cancer (ACC), we noted a discrepancy within several patients between the specific physical functioning scores of the QLQ-C30 (QLQ-C30 PF) as reported by patients and the WHO PS as scored by physicians, while these items in principle should have a similar result.

We therefore performed an overall comparison on the prognostic value in terms of overall survival (OS) between the WHO PS as assessed by the treating physicians and the baseline QLQ-C30 PF as reported by patients. We then validated our results in a subsequent phase 3 study in ACC, the CAIRO2 study [11].

2. Materials and methods

2.1. Study design

We retrospectively compared the prognostic value for median OS of the WHO PS as reported by the treating physicians with the QLQ-C30 PF as reported by patients.

2.2. Patient population

ACC patients who participated in the randomised phase 3 CAIRO trial were used for this analysis, ClinicalTrials.govNCT00312000[10]. In this trial, 820 previously untreated ACC patients were randomised between two arms: (1) sequential treatment with capecitabine, irinotecan and capecitabine plus oxaliplatin and (2) upfront combination treatment with capecitabine plus irinotecan followed by capecitabine plus oxaliplatin. Stratification parameters included WHO PS (0–1 versus 2), prior adjuvant treatment (yes versus no), serum lactate dehydrogenase (LDH) value (normal versus abnormal), predominant localisation of metastases (liver versus extrahepatic) and treatment centre. The primary end-point was OS, secondary end-points included QoL. The final results did not show a significant difference in median OS between the two treatment arms. QoL evaluation was a prospective part of the study, which for financial reasons was limited to the first 635 patients that were included in the study. All patients who completed a baseline QoL questionnaire were included in this analysis.

We validated our results in the CAIRO2 study, in which the addition of cetuximab to a regimen of capecitabine, oxaliplatin and bevacizumab was investigated in ACC patients, ClinicalTrials.govNCT00208546[11]. CAIRO2 included patients with WHO PS 0–1, and baseline QLQ-C30 was also a prospective part of the study.

2.3. Measures

Both CAIRO and CAIRO2 study required the assessment of WHO PS by the treating physician of all patients prior to randomisation (Table 1). Patients were asked to complete the baseline EORTC QLQ-C30 [12] questionnaire prior to randomisation and every three cycles thereafter until disease progression. For the current analysis, we used the baseline scores of the answers to the five questions of the QLQ-C30 PF (Table 2). Other scores of the QLQ-C30 were not analysed. We classified patients as having poor physical functioning when three or more questions were answered with ‘quite a bit’ or ‘very much’. Patients who did not meet this criterion were classified as having good physical functioning. With the formula of the EORTC QLQ-C30 PF, scores were calculated according to the EORTC QLQ-C30 manual [13]. By this calculation, a good score should then be more than 66.7% and a poor score 66.7% or less. The scores of the physical functioning were then used to divide patients for each of the three WHO PS groups (0, 1 and 2) into two groups: those with either ‘good’ or ‘poor’ QoLPF, resulting in a total of six groups.

Table 1

WHO performance status.

 

Grade Description
0 Able to carry out all normal activity without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out light work
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 Dead

Table 2

Physical functioning items of the EORTC QLQ-C30.

 

fx1 EORTC QLQ-C30 (version 3.0.) Not at all A little Quite a bit Very much
1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase? 1 2 3 4
2. Do you have any trouble taking a long walk? 1 2 3 4
3. Do you have any trouble taking a short walk outside of the house? 1 2 3 4
4. Do you need to stay in bed or a chair during the day? 1 2 3 4
5. Do you need help with eating, dressing, washing yourself or using the toilet? 1 2 3 4

2.4. Statistics

OS was estimated using the Kaplan–Meier method and was compared using the log-rank test. All tests were two sided with an alpha of 5%. A multivariate Cox regression model was used to test which scoring system had a better prognostic value, WHO PS or QLQ-C30 PF. The other variables entered in this model were the factors that were found prognostic in the retrospective analysis of the CAIRO study: serum LDH (normal versus elevated), number of metastatic sites (1 versus more than 1), resection of the primary tumour and treatment arm [10] and [14].

The same method and analysis was performed in the CAIRO2 trial. All analyses were performed using Stata 13.1.

3. Results

A total of 556 patients included in the CAIRO trial completed a baseline QoL form. One patient had to many PF items missing; therefore, 555 patients were eligible for this analysis. Patients with WHO PS 0, 1 and 2 had a median OS of 18.9, 14.7 and 12.9 months, respectively (p < 0.001, Fig. 1). Patients with ‘good’ and ‘poor’ QLQ-C30 PF had a median OS of 19.3 and 10.2 months, respectively (p < 0.001, Fig. 2). Next, we combined the results of WHO PS and QoL scores (Table 3). The median OS for patients with a ‘good’ versus a ‘poor’ QLQ-C30 PF of patients with a WHO PS 0 was 20.3 months (n = 300) and 10.4 months (n = 44), respectively. For patients with WHO PS 1, this was 16.1 months (n = 126) and 10.1 months (n = 63), respectively, and for patients with WHO 2 16.2 months (n = 11) and 9.9 months (n = 12), respectively (Table 3, Fig. 3).

Fig. 1

Fig. 1

Overall survival for WHO PS 0 (median, 18.9 months; 95% CI: 17.3–21.0), 1 (median, 14.7 months; 95% CI: 12.2–17.3) and 2 (median, 12.9 months; 95% CI: 4.2–21.6). CI, confidence interval.

 

Fig. 2

Fig. 2

Overall survival for ‘good’ QoL (median, 19.3 months; 95% CI: 17.9–20.5) versus ‘poor’ QoL (median, 10.2 months; 95% CI: 8.5–12.2). CI, confidence interval; QoL, quality of life.

 

Table 3

Overall survival for patients with good versus poor QoL within the subcategories of patients with WHO 0, 1 and 2.

 

WHO PS QLQ-C30 PF Total N (%) Median OS (months) 95% Confidence interval
Lower bound Upper bound
0 Good QoL 300 (54) 20.3 18.2 21.9
Poor QoL 44 (8) 10.4 6.5 17.1
1 Good QoL 125 (23) 16.8 14.0 19.8
Poor QoL 63 (11) 10.1 6.6 12.2
2 Good QoL 11 (2) 16.2 4.6 23.1
Poor QoL 12 (2) 9.9 3.6 22.2

QoL, quality of life; OS, overall survival.

Fig. 3

Fig. 3

Overall survival of WHO PS and ‘good’ QoL versus ‘poor’ QoL. QoL, quality of life.

 

In a multivariate Cox regression model which included baseline serum LDH, number of metastatic sites, resection status of the primary tumour and treatment arm, a ‘good’ versus ‘poor’ QLQ-C30 PF score was significantly prognostic for OS (hazard ratio [HR], 0.57 [95% confidence interval {CI}: 0.46–0.72]) as was serum LDH with a HR of 0.56 (95% CI: 0.46–0.67), but not WHO PS (WHO PS 0 versus 1 HR 0.85, 95% CI: 0.69–1.02; WHO PS 0 versus 2 HR 0.87, 95% CI: 0.54–1.39, Table 4).

Table 4

Multivariate Cox regression model for overall survival.

 

Variables HR 95% CI p-Value
Serum LDH normal versus elevated 0.56 0.46–0.67 0.000
QLQ-C30 PF good versus poor 0.57 0.46–0.72 0.000
Number of metastatic sites 1 versus >1 0.72 0.61–0.87 0.001
WHO PS
 0 versus 1 0.85 0.69–1.0.2 0.09
 0 versus 2 0.87 0.54–1.39 0.56
Resection primary tumour (yes versus no) 0.76 0.61–0.95 0.02
Treatment arm (sequential versus combination chemotherapy) 0.92 0.77–1.1 0.36

HR, hazard ratio; CI, confidence interval; LDH, lactate dehydrogenase.

In the CAIRO2 trial, 699 of the 755 randomised patients completed a baseline QoL form. Patients with WHO PS 0 and 1 had a median OS of 22.2 and 17.1 months, respectively (p = 0.004). Patients with ‘good’ and ‘poor’ QLQ-C30 PF had a median OS of 22.0 and 15.2 months, respectively (p < 0.001). The median OS of patients with a ‘good’ versus a ‘poor’ QLQ-C30 PF in the group of patients with WHO PS 0 was 23.5 months (n = 377) and 18.9 months (n = 183), respectively, and in the group of patients with WHO PS 1 17.1 months (n = 61) and 14.2 months (n = 78), respectively (Table 5.). In a multivariate Cox regression model which included the same variables as in the CAIRO analysis, a ‘good’ versus ‘poor’ physical functioning was significantly prognostic for OS (HR, 0.68 [95% CI: 0.55–0.84]), but not WHO PS (WHO PS 0 versus 1 HR 0.89, 95% CI: 0.74–1.07, Table 6).

Table 5

Overall survival for patients with good versus poor QoL within the subcategories of patients with WHO 0 and 1 in the CAIRO2 study.

 

WHO PS QLQ-C30 PF Total N Median OS (months) 95% Confidence interval
Lower bound Upper bound
0 Good 377 (54%) 23.5 21.7 25.9
Poor 61 (9%) 17.1 12.0 22.0
1 Good 183 (26%) 18.9 16.4 21.3
Poor 78 (11%) 14.2 10.9 17.4

QoL, quality of life; OS, overall survival.

Table 6

Multivariate Cox regression model for overall survival in the CAIRO2 study.

 

Variables HR 95% CI p-Value
Serum LDH normal versus elevated 0.68 0.57–0.81 0.001
QoL good versus poor 0.68 0.55–0.84 0.000
Number of metastatic sites 1 versus >1 0.72 0.59–0.87 0.001
WHO PS 0 versus 1 0.89 0.74–1.07 0.21
Resection primary tumour (yes versus no) 0.80 0.64–1.00 0.05
Treatment arm (CB versus CBC) 0.85 0.72–1.01 0.074

QoL, quality of life; HR, hazard ratio; CI, confidence interval; LDH, lactate dehydrogenase; CB, chemotherapy + bevacizumab; CBC, chemotherapy + bevacizumab + cetuximab.

4. Discussion

The CAIRO study investigated the optimal use of standard chemotherapy regimens in patients with ACC. During the analysis of the data from this study, we sometimes observed a discrepancy between the WHO PS as scored by physicians and the five physical functioning items from the EORTC QLQ-C30 as scored by patients. For example, a patient with a WHO PS score of 0 reported that he had quite a bit trouble taking a short walk. Therefore, we performed an overall comparison of physician- versus patient-reported physical performance in relation to the median OS. Although WHO PS and QLQ-C30 PF each showed a significant difference in median OS between their respective subgroups, QLQ-C30 PF but not WHO PS was a significant prognostic factor in multivariate analysis. These results were confirmed in the CAIRO2 study.

The clinical relevance of this finding is that within each category of patients with WHO PS 0, 1 and 2, a large difference in median OS was observed between patients with a good and a poor QLQ-C30 PF. For instance, 13% of patients (44 out of 344) with a WHO PS score of 0 had a poor QLQ-C30 PF and had a worse survival as compared to the 66% of WHO PS 1 patients with good QLQ-C30 PF. QLQ-C30 PF was also a relevant discriminating factor within the group of patients with PS 1 and PS 2, although within the latter category, the number of patients was small. Therefore, our results show a better prognostic value for PRO concerning physical functioning as measured by the physical functioning scale of the EORTC QLQ-C30 compared to the physician-rated WHO PS. Patients with both WHO PS 0 or 1 and good QLQ-C30 PF had the best survival, while patients with a WHO PS 0 but a poor QLQ-C30 PF had comparable survival to patients with a WHO PS 2. The prognostic value of serum LDH was comparable to QLQ-C30 PF 0, with a HR of 0.56 (95% CI: 0.46–0.67). We have confirmed these results in the CAIRO2 study for patients with WHO PS 0 and 1 by multivariate analysis.

PROs were found to be prognostic in several other studies [8], [15], [16], [17], and [18]. Gotay et al. systematically assessed the impact of various PROs on patient survival in 39 clinical trials in different tumour types and concluded that PROs might be considered for stratification purposes in future trials, as they were often better predictors of survival than PS. Quinten et al.[8] assessed prognostic significance of sociodemographic and clinical variables and the QLQ-C30 with Cox proportional hazard models in a meta-analysis of 30 different trials also in different tumour types. They found physical functioning, pain and appetite loss to be prognostic in addition to sociodemographic and clinical measures. Efficace et al.[7] showed that social functioning as measured by the social functioning scale of the EORTC QLQ-C30 acted as an important prognostic measure for survival beyond a number of previously known biomedical parameters in metastatic colorectal cancer [7]. Since we analysed the prognostic value of physician versus patient-assessed physical performance, we only used the questions of the physical functioning part of the QoL-C30 because we considered these questions as the best surrogate for WHO PS.

An important limitation of scoring PS and QLQ-C30 PF remains their subjective nature, which may occur at the side of both the physician and the patient. Blagden et al.[19] studied the agreement in assessment of the ECOG PS among patients and their physicians. Physicians were more likely to assign a better score to patients than patients did to themselves. This was confirmed by Schnadig et al.[20]. However, these subjective parameters can be validated by objective outcome measures such as OS. Although we and others show that PS assessed by patients and physicians is significantly associated with survival, our data strongly support the superiority of patient-reported baseline QoL to physician-assessed WHO PS.

In conclusion, physical functioning as assessed by patients using the EORTC QLQ-C30 PF is more prognostic than WHO PS as scored by physicians. Our data suggest to include the results of baseline physical functioning of the EORTC QLQ-C30 PF instead of WHO PS as a stratification parameter in oncology trials.

Conflict of interest statement

None declared.

Acknowledgements

This work was supported by the Dutch Colorectal Cancer Group, the Netherlands Cancer Organisation, location Nijmegen, The Netherlands, and an unrestricted scientific grant from Sanofi-Aventis.

References

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Footnotes

a Clinical Trial Department, Netherlands Comprehensive Cancer Organisation (IKNL), The Netherlands

b Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands

c Department of Medical Oncology, University Medical Centre, Utrecht, The Netherlands

d Department of Medical Oncology, Academic Medical Center, University of Amsterdam, The Netherlands

Corresponding author: Department of Medical Oncology, Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands. Fax: +31 206919743.


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