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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2020-2026 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.3117 Validation of Patient's Self-Reported Social Functioning As an Independent Prognostic Factor for Survival in Metastatic Colorectal Cancer Patients: Results of an International Study by the Chronotherapy Group of the European Organisation for Research and Treatment of Cancer
From the European Organisation for Research and Treatment of Cancer Data Center, Quality of Life Unit; Hôpital Universitaire St-Luc, Université Catholique de Louvain, Brussels; Centre Hospitalier Chrétien-Clinique Saint-Joseph, Departement d'Oncologie Medicale, Liege, Belgium; Institut National de la Santé et de la Recherche Médicale, U776, Rythmes Biologiques et Cancers; Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif; Université Paris-Sud, UMR-S0776, Orsay; Centre Hospitalier Universitaire Dupuytren, Oncologie Médicale, Limoges, France; The Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario, Canada; Azienda Ospedaliera "Santa Maria degli Angeli", Pordenone; University of Turin, San Luigi Hospital, Regione Gonzole 10, Orbassano; and the Istituto Regina Elena, Department of Medical Oncology, Rome, Italy Corresponding author: Fabio Efficace, PhD, Italian Group for Adult Hematologic Diseases (GIMEMA), GIMEMA Data Center, Health Outcome Research Unit, Via Benevento, 6, 00161, Rome, Italy; e-mail: f.efficace{at}gimema.it
Purpose A recent study identified a prognostic model for survival in metastatic colorectal cancer patients which included WBC count, alkaline phosphatase (AP), number of metastatic sites, and patients’ self-reported social functioning. The aim of this research is to validate this model on data from an independent sample. Patients and Methods This validation study is based on a prospective randomized controlled trial in patients with metastatic colorectal cancer conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Chronotherapy Group. Overall, 564 patients in 10 countries were enrolled. For the purpose of this independent validation, patients with health-related quality of life (HRQOL) baseline data were analyzed. HRQOL was assessed using the EORTC Quality of Life Questionnaire C30 (QLQ-C30). The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. Results The previous model with an additional adjustment, by stratification for sex, was replicated and its parameters were confirmed to independently predict survival: WBC count with an hazard ratio (HR) of 1.31 (95% CI, 1.021 to 1.698; P = .034); AP with an HR of 1.53 (95% CI, 1.188 to 1.979; P = .001); number of sites involved with an HR of 1.90 (95% CI, 1.531 to 2.364; P < .0001); and patients’ self-reported social functioning with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001). The latter translates into a 6% increase in the likelihood of an earlier death for every 10-point decrease in the social functioning scale of the EORTC QLQ-C30. Conclusion This study provides confirmatory evidence of the independent prognostic value of patients’ self-reported social functioning in patients with advanced colorectal cancer.
A growing body of literature is showing that patients’ perception of their own health status, as measured by multidimensional measures of health-related quality of life (HRQOL), can provide independent prognostic information beyond that of traditional biomedical data. The identification of patient-reported HRQOL parameters with independent prognostic value for survival outcomes, for example, could have important implications for routine clinical practice and clinical research. This information could help facilitate the routine treatment decision-making process, perhaps enabling physicians provide patients with more timely treatment interventions. It could also help to better stratify patients included into randomized controlled trials. The potential value of HRQOL as a key prognostic factor has recently emerged in more than 50 studies.1 This evidence has been shown in several advanced cancer populations including bladder,2 breast,3,4 colorectal,5,6 esophagogastric,7,8 head and neck,9,10 hepatocellular,11 melanoma,12 myeloma,13,14 and lung cancer.15-17 However, findings regarding which specific HRQOL parameter is the best predictor in a given cancer population need to be confirmed in independent samples as different results have been observed and no independent validation studies have been published. It is crucial to validate previously constructed prognostic models on independent samples of patients.18,19 A recent large study (European Organisation for Research and Treatment of Cancer [EORTC] 40952)6 showed the independent prognostic value of pretreatment patients’ self-reported social functioning in a population of chemotherapy-naïve patients with advanced colorectal cancer treated with fluorouracil (FU)-based chemotherapy. The final multivariate model of this study also identified WBC count, alkaline phosphatase, and number of metastatic sites to independently predict overall survival (OS).6 This final model was also internally validated using a bootstrap resampling procedure to investigate model selection stability20 confirming this one as being the most adequate model.6 The objective of this study is to validate the above reported prognostic model (EORTC 40952)6 on an independent data set of patients with similar baseline characteristics and to confirm the independent prognostic value of patients’ self-reported social functioning. To our knowledge, this is the first validation study investigating the independent prognostic value of a patient's self-reported HRQOL parameter using exactly the same methodology on an independent sample of patients with cancer.
Study Design This work is based on data from a prospective multicenter randomized controlled trial in previously untreated patients with metastatic or recurrent colorectal cancer, conducted by the EORTC Chronotherapy Group (EORTC study 05963).21 Overall, 564 patients from 36 centers in 10 countries were enrolled. Two hundred eighty-two patients were randomly assigned to receive a chronomodulated infusion of FU, leucovorin, and oxaliplatin for 4 days (ChronoFLO4) and 282 patients received a conventional 2-day delivery of the same drugs (FOLFOX2). The primary end point of the trial was 2-year survival rate; HRQOL was a secondary end point. Median survival did not differ significantly between both treatment arms. However, a significant and independent sex per treatment schedule interaction was demonstrated. Women treated with ChronoFLO4 had a median survival that was significantly poorer than those receiving FOLFOX2 (P = .03), while men treated with ChronoFLO4 had significantly better survival than those receiving FOLFOX2 (P = .02). Full details have been previously reported.21 Given the above results, stratification for treatment arm and sex was added for all survival analysis in this validation study. We used the HRQOL data collected at baseline in this study as a validation data set for the multivariate prognostic model that had been previously developed for the EORTC 40952 study.6
Patients
HRQOL Assessment Ten scales of the EORTC QLQ-C30, as previously identified in the original study (EORTC 40952),6 were selected a priori for this analysis: physical, emotional, and social functioning; fatigue; nausea/vomiting; pain; appetite loss; constipation; diarrhea; and the global health status/QOL scale. These baseline HRQOL parameters were also compared with the original study (EORTC 40952)6 to investigate if there were any differences in the two populations in terms of HRQOL.
Patient Demographics and Biomedical Data
Statistical Analysis
Main Biomedical Characteristics of Study Populations Of the 564 patients enrolled in the EORTC 05963 trial, 443 provided valid HRQOL baseline questionnaires (78.5%), which were used for the purpose of this study. There were no differences in the main clinical characteristics between patients with and without HRQOL baseline data, as well as no difference in terms of OS, the median being 19.5 and 18.7 months, respectively (P = .193). Of the 443 patients, 220 received FOLFOX2 (49.7%) and 223 received ChronoFLO4 (50.3%). With 354 observed deaths and a reported overall median survival time of 19.5 months, the data were sufficiently mature to conduct an adequately powered analysis. The proportional hazards assumptions were found to be valid for the selected prognostic variables. Most of the clinical characteristics of patients enrolled in this validation study (EORTC 05963) were similar to those in the original study (EORTC 40952).6 However, in this validation study, fewer patients were accrued with rectal primary tumors (24% v 50%) and more patients were accrued with a single metastatic site (50% v 27%). Median survival of patients enrolled in this confirmatory study was higher, being 19.5 months (95% CI, 18.3 to 20.8 months) compared with the median survival of patients in the original study (EORTC 40952)6 where the median survival was 14.2 months (95% CI, 12.1 to 16.2 months). Details are reported in Table 1.
HRQOL Baseline Characteristics of Study Populations HRQOL scores in this population were very similar to those of the original study (EORTC 40952),6 without any clinically meaningful difference (ie, > 10 points28) in the selected scales of the EORTC QLQ-C30 between the two populations (Table 2). In both studies, patients reported near identical scores (± standard deviation) on the social functioning scale, these being 75.7 (± 29.1) and 75.4 (± 29.2) for this validation and the original study (EORTC 40952),6 respectively.
To investigate the magnitude of the association between social functioning and other outcomes in both studies, pairwise correlations were calculated and results are reported in Table 3.
Distribution of HRQOL scores was also investigated in the two treatment arms (ChronoFLO4 v FOLFOX2) and in both sexes of patients included in the validation data set and these were similar (data not shown).
Relationships Between Patient-Reported HRQOL Parameters and Survival (Survival Prognostic Model)
The final multivariate model previously identified in the original study (EORTC 40952)6 was applied to this independent sample (EORTC 05963). All of the traditional parameters previously identified to be independent prognostic factors (ie, WBC count, alkaline phosphatase, and number of metastatic sites) were confirmed in this validation data set. Also, patients’ self-reported social functioning was confirmed to be a key independent prognostic factor with an HR of 0.94 (95% CI, 0.905 to 0.976; P = .001) and a 10-point shift worse on this scale translated into 6% increase in the likelihood of an earlier death. Details on comparisons of the two prognostic models are reported in Table 5. A sensitivity analysis using only treatment as stratification factor in the final Cox model yielded similar results. The HRs of an earlier death corresponding to baseline social functioning were similar (P < .01) whether Cox analyses were performed with stratification for treatment (HR, 0.941), for treatment and sex (HR, 0.940), or without such stratifications (HR, 0.943). Harrell's C-indices18 were also calculated for the presented Cox model with and without social functioning as a factor, revealing an improvement from 0.629 to 0.648 in predictive power. The C-indices for the model without sex and/or treatment as stratification factors remained unchanged at 0.648 indicating there was no inflation due to the stratification.
Survival curves based on social functioning scale terciles are reported in Figure 1 for descriptive purposes. Patients scoring below the lower tercile functioning score (< 60 points) had a median survival of 13.5 months as compared with patients scoring in the middle (  60 and < 100) or the upper tercile (= 100), who had a median survival of 20.9 and 20.8, respectively (overall test, P < .001). This translated into a 2-year survival rate of 22% versus 42% versus 43% for the lower, middle, and upper tercile of the social functioning score, respectively. Details are reported in Figure 1.
The independent prognostic value of patients’ self-reported social functioning, estimated with the EORTC QLQ-C30, was validated on a large and independent population of patients with advanced colorectal cancer. At baseline, this variable investigates how the disease burden has limited a patient's social interactions with the following two questions: "has your physical condition or medical treatment interfered with your family life?" and "has your physical condition or medical treatment interfered with your social activities?" While previous prognostic factor studies have shown the independent prognostic value of patients’ judgment of their own health status for survival in various advanced cancer diseases, to our knowledge, no validation study has as yet been published on an independent sample involving a similar cancer patient population and using the same HRQOL multidimensional questionnaire. This confirmatory study therefore provides robust supportive evidence that social functioning represents an important prognostic variable in patients with advanced colorectal cancer.6 This study has a number of strengths including a large international sample of patients (N = 443) recruited in a multicontinental prospective randomized trial with sufficient follow-up and mature survival data allowing for an adequately powered analysis. There was no difference in terms of survival between patients with and without baseline HRQOL data, thus ensuring the population analyzed for this validation study was representative of the overall trial population (EORTC 05963). Data collection in this sample was of high quality with HRQOL measured with a psychometric robust questionnaire and main clinical data available for all patients. In addition, the biomedical characteristics and HRQOL data were similar both in this study population and in that of the original study (EORTC 40952),6 thus lending credit to our attempt to validate the previously identified multivariate model. The proportion of patients with more than one metastatic site was inferior (50% v 73%) and oxaliplatin was added to FU and leucovorin in this study as compared with the original sample.6 These differences most likely accounted for the OS differences between both trials. The median survival of patients was 14.2 months in the original study (EORTC 40952)6 and 19.5 months in this sample. The reduction in the patients’ risk of death for any 10-point increase in social functioning scale (ie, a better score) was 9% in the original study (EORTC 40952)6 and 6% in this confirmatory study. This slight decrease in the HR could be influenced by the different median survival of patients included in this trial when compared with those in the previous one (19.5 v 14.2 months). This finding could be supported by previous evidence suggesting that HRQOL parameters are more likely to provide independent prognostic information in advanced cancer diseases, but not in patients with earlier stage disease.29-32 Previous work has discussed possible mechanisms underlying the association between patients’ self-perception of HRQOL parameters and survival outcomes.30-34 While the relationship between social functioning and survival of patients with colorectal cancer is not immediately clear, there is previous evidence suggesting that social functioning is a sensitive aspect of HRQOL in this cancer population. Anthony et al35 investigated the prognostic value of a number of pretreatment HRQOL parameters for surgical complications in colorectal patients undergoing open surgical resection for colorectal cancer and found that an improved social functioning score (measured by the Medical Outcomes Study Short Form-36) was independently associated with a decreased likelihood of surgical complications in the multivariate analysis. Arndt et al36 compared HRQOL in patients with colorectal cancer 1 year after diagnosis with that of a general population using the same measure of our study (the EORTC QLQ-C30) and showed that social functioning was the most impaired HRQOL domain out of all the other functional and global health status scales. With the aim of investigating whether HRQOL limitations continued to persist over a longer period, the same authors conducted a population-based study investigating this issue 3 years after diagnosis of colorectal cancer and confirmed that social functioning was still the most affected HRQOL domain out of the remaining functional and global health status scales measured with the EORTC QLQ-C30.37 Overall, these results are in line with our findings—in our validation sample, social functioning was also the most impaired aspect out of all the other functional and global health status scales when compared with data of a general population. The mean social functioning score in our study was 15.3 points poorer than that found in a general noncancer population.38 Our study has limitations. Given the design of our project, we were not able to investigate further the nature of the link between a patient's self-reported social functioning and survival. It is also possible that other different variables than social functioning would have emerged in the multivariate analysis had one been undertaken de novo rather than entering the variables from the final multivariate model identified in the original study (EORTC 40952).6 Although future research could investigate the underlying mechanism of the association between social functioning and length of survival, our data indicate that, in the very least, this specific HRQOL domain seems to capture the whole burden of the disease in a way which is not usually assessed by traditional medical indices commonly used in routine oncology practice. In our study, there were no major correlations between patients’ self-reported social functioning and other traditional clinical data, however, the highest correlation was found with performance status. The evidence that a patient's own health status judgment provides a unique perspective, as well as independent prognostic information, could also greatly further support the need to move toward a more patient-centered approach as has also been recently highlighted to be crucial in the context of quality care.39 In conclusion, for the first time the independent prognostic value of patients reported social functioning at baseline has been observed and now confirmed in two separate, international, prospective large data sets of chemotherapy-naïve patients with advanced colorectal cancer. Therefore, present findings support the investigation of underlying biologic mechanisms, as well as the collection of patient-reported HRQOL data in routine clinical practice, because these could provide valuable prognostic information.
The author(s) indicated no potential conflicts of interest.
Conception and design: Fabio Efficace, Andrew Bottomley, Christian Focan, Sylvie Giacchetti, Francis Lévi Financial support: Francis Lévi Administrative support: Fabio Efficace, Andrew Bottomley Provision of study materials or patients: Pasquale F. Innominato, Georg Bjarnason, Yves Humblet, Salvatore Tumolo, Dominique Genet, Marco Tampellini, Carlo Garufi, Christian Focan, Francis Lévi Collection and assembly of data: Fabio Efficace, Pasquale F. Innominato, Dominique Genet, Carlo Garufi, Christian Focan, Sylvie Giacchetti, Francis Lévi Data analysis and interpretation: Fabio Efficace, Pasquale F. Innominato, Georg Bjarnason, Corneel Coens, Andrew Bottomley, Christian Focan, Sylvie Giacchetti, Francis Lévi Manuscript writing: Fabio Efficace, Pasquale F. Innominato, Georg Bjarnason, Corneel Coens, Francis Lévi Final approval of manuscript: Fabio Efficace, Pasquale F. Innominato, Georg Bjarnason, Corneel Coens, Yves Humblet, Salvatore Tumolo, Dominique Genet, Marco Tampellini, Andrew Bottomley, Carlo Garufi, Christian Focan, Sylvie Giacchetti, Francis Lévi
We thank all the patients who kindly agreed to participate into this study and all the investigators for their involvement.
Supported in part by the Associazione Italiana per la Ricerca sul Cancro; by Grants No. 2U10 CA11488-31 through 5U10 CA11488-35 from the National Cancer Institute (Bethesda, MD); by the EORTC Charitable Trust; the Chronotherapy Group is now operating under the auspices of the "International Association for Research on Time in Biology and Chronotherapy" (ARTBC International), Paul Brousse Hospital, Villejuif, France. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Presented at the 14th Annual Conference of the International Society for Quality of Life Research, Toronto, Canada, October 10-13, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
