Defining cancer-related fatigue for biomarker discovery

Cancer-related fatigue (CRF) is a prominent and distressing symptom for cancer patients that can impair their overall health-related quality of life [1]. CRF is often described as a complex and multidimensional concept consisting of physical, cognitive, affective, spiritual, psychosocial, and environmental factors [1, 2]. Assessment of CRF is obtained from responses on various valid, self-report questionnaires established from several theoretical models of CRF. The complexity of CRF as a concept and the variability in the method of CRF assessment pose a challenge to investigators attempting to understand the etiology of CRF. Establishing a clear definition of a phenomenon, such as CRF, is an essential starting point for phenotypic characterization and biomarker discovery [3]. Therefore, this commentary aims to increase our awareness of the need for better definition and clearer phenotypic characterization of CRF. Several organizations have proposed definitions for CRF such as the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Pan Canadian Practice Guidelines [2, 4, 5]. However, a recent review conducted by the Multinational Association of Supportive Care in Cancer Fatigue Study Group– Biomarker Working Group found that CRF is defined in various ways [6]. Some studies referenced a specific definition used by national organizations such as the National Comprehensive Cancer Network [2], while other studies defined CRF using specific cancer treatment-related tools, such as the National Cancer Institute Common Toxicity criteria, as well as diagnostic criteria from a proposed ICD-10 definition of CRF [7, 8]. The lack of a consistent operational definition for CRF in the empirical literature makes it challenging to develop a CRF phenotype, which in turn poses a major obstacle for researchers investigating the biological mechanisms of CRF [9]. Therefore, consistent use of an agreed upon definition would be of benefit for biomarker discovery. In addition to the variability in the definition of CRF, numerous questionnaires were reported in the reviewed articles to assess CRF. In fact, 23 different questionnaires were used to assess CRF in the 47 articles reviewed. Even when the same questionnaire was used, different scoring rubrics were often applied to phenotype CRF or to determine its clinical relevance [10, 11]. The significance of this variability when investigating different biologic pathways to determine molecular correlates of CRF is pronounced. For example, we recently assessed genetic correlates of CRF using two different cut-off scores on the Functional Assessment of Cancer TherapyFatigue (FACT-F) questionnaire (http://www.facit.org/ FACITOrg/Questionnaires) in the same group of men with prostate cancer who received radiation therapy. The FACT-F subscale is a 13-item widely-used, readily available questionnaire validated to explore fatigue symptoms in the oncology population. Our unpublished findings revealed that different functional biologic pathways were found when different approaches were utilized to phenotype CRF patients using previously reported FACT-F cut-off scores (Fig. 1). Investigating causal relationships of CRF with specific physiologic mechanisms will remain difficult, unless the complex concept of CRF is better defined, and clearly phenotyped. Perhaps, describing the disease and/or treatment associated with the CRF experience can better define the construct, especially if the intention is for biomarker discovery. CRF is often believed to be induced by the tumor itself and/or the * Leorey N. Saligan saliganl@mail.nih.gov