Sorafenib is a multi-target tyrosine kinase inhibitor that inhibits tumor proliferation and angiogenesis.3,7,18,19 The formulation has mild to moderate toxicity and a variety of solid tumors are resistant to it.7,20 This is the first systemic drug that has been shown to prolong the survival of liver cancer patients in two phase III trials.6,7,20 It is now the standard for systemic treatment in patients with advanced liver cancer.13,21–24 To prolong the survival of patients with advanced liver cancer, the initial dose of sorafenib recommended in the treatment is 800 mg/day. However, since the incorporation of sorafenib into clinical applications, and because of the intolerable side effects, a lower initial dose has been reported, with starting dose of 800 mg/day that decreases to 400 mg/day, or a starting dose of 400 mg/day. A large number of reports have reported side effects in patients such as hand-foot reactions as well as the effects of drug dosage on patient survival due to intolerable side effects.17,23,25 There have been few reports of patients suffering from fatigue due to sorafenib. This article explores and elaborates these issues.

At present, it is believed that the fatigue experienced by patients with liver cancer is mainly due to the weak constitution of the patient, the dyscrasia caused by the tumor, the side effects caused by the drug itself, the tumor burden26 and the psychological state of the patient, but the exact mechanism of its occurrence is still not clear.12 Fatigue is one of the common adverse reactions to sorafenib. Therefore, studies on the drug-related fatigue would have a greater impact on the survival of patients with advanced hepatocellular carcinoma.27,28 Drug-related fatigue is different from tumor-related fatigue. The so-called tumor-related fatigue refers to the continuous subjective fatigue caused by the treatment for the tumor or the tumor itself. It has nothing to do with the daily activities of the patient. Furthermore, tumor-related fatigue affects the patient’s activities and their restfulness. During post-remission therapy; drug-related fatigue is caused by the side effects of the drug, and changes the dosage of the drug can improve fatigue. Here, our team analyzed 182 patients from our hospital. The fatigue was related to tumor burden and physical fitness, and most patients could adjust the dose to reduce fatigue.

In clinical practice, treatment-related fatigue is a painful and disabling disease that is often underreported, misled and under-managed.10–13,20 Studies have shown that fatigue was the most common side effect, leading to a dose reduction or even treatment interruption.3,4 Patients, especially the elderly and infirm, are more susceptible to the drug’s toxicity, and studies have shown that they may be associated with more comorbidities or poor nutrition.1,19,22 An analysis of the patient’s fatigue-related indicators can guide a customized treatment plan for the patient and reduce the risk of fatigue-related dose reduction or treatment interruption. Therefore, the determination of risk factors for fatigue may allow for early management in the most susceptible patients. At the same time, the new and simpler classification method in this paper is more conducive to clinical practice.

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After regrouping the patients, the patients were analyzed by chi-square test. The ECOG PS of the two groups were different before or after treatment with the drug. The patients with severe fatigue had larger tumor burdens, while the patients with less fatigue had better hand-foot reactions. The above results are in line with the current mainstream views.9,17,23,24

In this study, patients taking sorafenib had TTP time (MST) of 10.7months (95% Cl: 9.3––12.1) and a total OS time (MST) of 19.0months (95% Cl: 15.5––22.5). In this clinical trial review, the prognosis of patients with hand-foot reaction was better; but the prognosis of patients with vascular invasion was poor, which was consistent with previous literature reports. After grouping the patients according to their fatigue level, Kaplan–Meier (Log rank test) was performed, followed by Cox analysis. The median OS times of patients with grades I, II, III fatigue were 20.9, 18.7 and 13.0 months, respectively. This indicated that the lighter the fatigue, the longer the overall survival time. Furthermore, of all patients, 158 (90.8%) patients a preoperative ECOG score ≤1, whereas 19 (83.1%) patients had an ECOG score of ≤1 after taking sorafenib. Overall, the patient’s fatigue was related to the administration of sorafenib. Good physical foundation is conducive to resistance to fatigue, so as to obtain a longer survival period.

According to the survival curve analysis and whether the patients can be grouped according to the fatigue of rest relief, the OS of the patients who were relieved of fatigue was 33.0±9.3 months, whereas the OS of the patients who could not be relieved of fatigue was 15.0±1.8 months. This difference was statistically significant. (P<0.000).Furthermore, the TTP of patients who were relieved of fatigue by rest was 20.9 months (95% Cl: 18.3–27.8), compared a TTP of 7.7months (95% Cl: 8.8–12.2) in patients who were not relieved of fatigue. This difference was also significantly different (P<0.000). Overall, fatigue relieved by rest is an important factor that affects the OS of patients.


Based on a study of 182 patients, treatment-related fatigue is an independent risk factor affecting the TTP and OS of patients with advanced hepatocellular carcinoma. The new and simpler classification method in this paper is more conducive to clinical practice.

Furthermore, approximately 59.3% of patients were unable to reduce their fatigue through rest, fatigue can seriously affect the prognosis of patients.

Ethics Approval and Consent

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All patients signed a written informed consent. The study was conducted in strict compliance with the Helsinki Declaration and was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (ethics approval number: QYFYEC 2013-021-01). All the participants and the contributors of this work have signed informed consent for publication.


This work was supported by The Affiliated Hospital of Qingdao University, Shandong Province, People’s Republic of China.

Author Contributions

Xuan Qiu and Liqun Wu collected patients’ data. Xuan Qiu analyzed the data and wrote the manuscript. Xuan Qiu and Liqun Wu conducted this study and revised the manuscript. All authors took part in the treatment of patients. All authors made substantial contributions to conception and design, acquisition of data or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.


There is no funding to report.


The authors report no conflicts of interest in this work.

Xuan Qiu, Manjiang Li, Liqun Wu, Yang Xin, Siyu Mu, Tianxiang Li, Kangjian Song

Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China

Correspondence: Liqun Wu
Liver Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Laoshan District, Qingdao, Shandong 266003, People’s Republic of China
Tel +86 15315328331
Email [email protected]


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Source: Cancer Management and Research.
Originally published September 4, 2020.

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