Incidence and Correlates of Fatigue in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review

Abstract

Prostate cancer is the second most common malignancy of men in the western countries. Fatigue is the most stressful symptom of which patients with metastatic castration-resistant prostate cancer (mCRPC) complain. The aim of this article was to report available data about the incidence of fatigue in mCRPC and its correlates. The design involved a systematic review to define incidence of fatigue according to Common Toxicity Criteria in randomized controlled trials of medical treatments of mCRPC and according to International Classification of Diseases Revision 10 (ICD-10) criteria, and to define prevalence and correlates of fatigue in patients with mCRPC. The data source used was PubMed. In December 2014, 2 PubMed searches were performed and the clinical data on the occurrence of cancer-related fatigue along the course of metastatic disease, and findings about its pathogenesis were summarized. Cancer-related fatigue, as defined according to ICD-10 criteria, was reported in 12% to 21% of patients, and prospective clinical trials showed a prevalence of Grade 3/4 fatigue according to Common Toxicity Criteria of 0% to 18%. A list of possible correlates of fatigue in mCRPC, either patient-related, disease-related, or treatment-related, is proposed herein for future studies. Antineoplastic treatments, particularly chemotherapy and radiotherapy, have a major role in the pathogenesis of fatigue in metastatic prostate cancer, however, hormonal treatments remain the most prevalent therapies. A standardized tool for multidimensional assessment of fatigue in metastatic cancer is suggested.

Introduction

Prostate cancer (PC) is the second most common cancer in men in the western countries. In 2008, in the European Union the estimated incidence was of 338,700 new cases, deaths were 70,800.¹ Approximately 10% to 20% of all patients with PC develop a metastatic castration-resistant PC (mCRPC) in the first 5 years after diagnosis.²

During the past 8 years a radical change in the horizon of care of mCRPC patients occurred. An improvement of overall survival (OS) has been reported from the use of at least 5 new drugs.3, 4, 5, 6, 7 However, if the new drugs delay and relieve some symptoms, their toxicity might increase the prevalence of other symptoms along the course of the disease.

Men with mCRPC experience physical and mental morbidity and impaired health-related quality of life (HRQoL) as a result of their disease and treatments. In a series of the predocetaxel era, when only 37% of patients received chemotherapy, it appeared that within 9 months a rapid and significant deterioration of HRQoL occurred.⁸ Many factors interfere with HRQoL, and then with OS,⁹ from the psychosocial symptoms such as depression and anxiety, to the adverse effects of regional treatments, such as erectile dysfunction, urinary and gastrointestinal symptoms, and those of androgen deprivation therapy (ADT) or diphosphonates.

Although pain is perhaps the most feared physical symptom, and occurs in 90% of cases and is linked to a skeletal event in 50% of cases, fatigue is the most common and distressing symptom of which mCRPC patients complain.10, 11 It is nominated by patients as the most important symptom to influence daily functioning.¹² Fatigue is a multifactorial condition, attributed to mCRPC, side effects of therapies, diminished activity, poor nutrition, depression, and comorbid conditions. Among 46 patients with PC of the Swedish Twin Registry the prevalence odds ratio of chronic fatigue was 2.24 (95% confidence interval, 0.98-5.10), second only to patients with lung cancer.¹³

To date, even if the International Classification of Diseases 10th Revision (ICD-10) definition of cancer-related fatigue (CRF) remains elaborate, as reported in Table 1,¹⁴ the multidimensional nature of CRF is more clear,15, 16, 17 in the same way as the different pathogeneses of CRF associated with metastatic cancer versus CRF of cancer survivors.¹⁸ Beyond the distinction between physical and mental domains of fatigue, an assessment of other domains could become necessary in the near future.17, 19, 20 In addition, in metastatic cancer the physical dimension of CRF prevails over the others, and various related factors, or correlates, affect CRF. Each of them has a different weight on the different fatigue dimensions.¹⁷ Biologically, the physical dimension appears to be better characterized according to C-reactive protein, interleukin-1 receptor antagonist, interleukin-6, neopterin, and serum tumor necrosis factor receptor-2 levels.¹⁸

The aim of the present review was to summarize the clinical data on the current occurrence of CRF along the course of mCRPC, and to report findings about pathogenesis and possible correlates of CRF in patients with mCRPC.