cancers Review Fatigue in Cancer Patients in Palliative Care—A Review on Pharmacological Interventions Caritha Klasson 1,2 , Maria Helde Frankling 1,2 , Carina Lundh Hagelin 3,4 and Linda Björkhem-Bergman 1,2, *   Citation: Klasson, C.; Helde Frankling, M.; Lundh Hagelin, C.; Björkhem-Bergman, L. Fatigue in Cancer Patients in Palliative Care—A Review on Pharmacological Interventions. Cancers 2021, 13, 985. https://doi.org/10.3390/cancers 13050985 Academic Editors: Mari Lloyd-Williams and Sebastiano Mercadante Received: 12 January 2021 Accepted: 22 February 2021 Published: 26 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Blickagången 16, Neo floor 7, SE-141 83 Huddinge, Sweden; caritha.klasson@ki.se (C.K.); maria.helde.frankling@ki.se (M.H.F.) 2 Palliative Medicine, Stockholms Sjukhem Foundation, Mariebergsgatan 22, SE-112 19 Stockholm, Sweden 3 Department of Health Care Sciences, Ersta Sköndal Bräcke University College, Palliative Research Centre, P.O. Box 11189, SE-100 61 Stockholm, Sweden; carina.lundh-hagelin@esh.se 4 Department of Neurobiology, Care Sciences and Society (NVS), Division of Nursing, Karolinska Institutet, Alfred Nobels Alle 23, SE-141 83 Huddinge, Sweden * Correspondence: linda.bjorkhem-bergman@ki.se; Tel.: +46-(0)-733-168462 Simple Summary: Cancer related fatigue is a common and distressing symptom for patients with cancer during and after primary treatment, and also in the palliative phase of the disease trajectory. This review focuses on the pharmacological treatment of cancer related fatigue in patients with advanced or metastatic cancer. There are few high-quality studies performed in this setting, but both methylphenidate and corticosteroids might be used to relieve fatigue. Abstract: Fatigue is one of the most distressing symptoms experienced by cancer patients. The suggested biological mechanism for cancer related fatigue (CRF) includes immune activation trig- gered by tumor tissue or by anticancer treatment but other mechanisms have also been proposed. Previous large meta-analysis of interventions on fatigue focuses mostly on patients early in the disease trajectory, with only one tenth of included studies performed in palliative cohorts. The aim of this narrative review is therefore to present a background on CRF with focus on the palliative setting. A summary of recent randomized, controlled trials on pharmacological interventions on CRF in palliative care is presented, including studies on psychostimulants, corticosteroids, testosterone and melatonin. Interestingly, in several of these studies there was a positive and similar effect on fatigue in both the intervention and the placebo arm—indicating an important placebo effect for any pharmacological treatment. In addition, studies on dietary supplements and on pharmacological complementary medicines are discussed. To conclude, the evidence is still weak for using pharmaco- logical treatments on CRF in palliative care patients—although methylphenidate and corticosteroids might be considered. Keywords: fatigue; palliative care; cancer; cancer related fatigue; clinical trials; therapeutics 1. Introduction 1.1. Cancer Related Fatigue Fatigue is one of the most distressing symptoms experienced by patients with cancer and has a high prevalence in cancer patients [1]. Fatigue can occur before, during and after treatment and persist for a long time [2,3]. Different definitions have been used, but today the most widely used definition stems from the National Comprehensive Cancer Network, NCCN, “Cancer-Related Fatigue is a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” [4]. The concept of fatigue as a multidimensional symptom has been challenged by the notion that fatigue rather should be regarded as a set of multiple symptoms to be addressed Cancers 2021, 13, 985. https://doi.org/10.3390/cancers13050985 https://www.mdpi.com/journal/cancers