Objective: To investigate the effects of fatigue on the survival of patients with advanced hepatocellular carcinoma treated with sorafenib.
Patients and Methods: A retrospective analysis of 182 cases of patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2017, showed clinical and pathological data and follow-up results. The clinical and pathological data as well as follow-up results of 182 patients with advanced hepatocellular carcinoma treated with sorafenib in our hospital from October 1, 2008, to October 31, 2018, were retrospectively analyzed. All patients were treated for at least 3 months. Patients were divided into three groups: fatigue grade I (n=74), fatigue grade II (n=62), and fatigue grade III (n=46), according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) version 5.0. Survival analysis between groups was performed by the Kaplan–Meier method (Log rank test), continuous variables were analyzed by t-test, and categorical variables were analyzed by chi-square test.
Results: The overall survival (OS) of patients who were relieved of fatigue was 33.0± 9.3 months, whereas the OS of patients who were not relieved of fatigue was 15.0± 1.8 months (P< 0.000). Furthermore, the time to progress (TTP) of patients who were relieved of fatigue by resting was 20.3 ± 10.9 months compared to a TTP of 7.7 ± 1.0 months in patients who were not relieved of fatigue (P< 0.000).
Conclusion: Patients, especially the elderly and infirm, were more susceptible to toxicity.

Keywords: hepatocellular carcinoma, sorafenib, fatigue, survival


Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide.1 The number of HCC deaths (approximately 800,000 per year) overlap with that of new cases, a testament to its high lethality.1,2 In recent years, with the advancement of diagnostic techniques and the improvement of surgical methods, the early diagnosis rate and resection rate of HCC have been improved, but even in patients with tumor resection, the recurrence rate after the resection is as high as 68%- 98%, the patient’s long-term prognosis is extremely poor.2

Sorafenib is a molecular targeted therapeutic. It is an oral multi-target, multi-kinase inhibitor that targets the serine/threonine kinase and receptor tyrosine on tumor cells and tumor blood vessels.3–5 Two Phase III clinical trials of Sorafenib, Sharp and Oriental, and Gideon have shown that sorafenib shows therapeutic effects in patients with advanced liver cancer and inoperable patients, and can improve the time to disease progression in patients with advanced hepatocellular carcinoma and Overall survival time.6,7

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Common adverse reactions to sorafenib include diarrhea, rash, scaling, fatigue, skin reactions in the hands and feet, hair loss, nausea, vomiting, itching, high blood pressure and loss of appetite. Fatigue is the most common symptom associated with cancer and cancer treatment. It is a subjective symptom, but objectively, under the same conditions, it will lose more or less its normal activities or work ability.8,9 This condition has a negative impact on the functional status of the cancer patient and the health-related quality of life (HRQoL), which affects many aspects of daily simple physical activity.8,10,11 Fatigue is a multifactorial process, and the precise underlying pathophysiology is still often unclear; therefore, many interventions for the treatment of this condition remain empirical.11–13 Among the underlying causes, anemia and hypothyroidism play an important role, accompanied by comorbidities such as cachexia. The onset of moderate or severe fatigue may have a serious impact on treatment, and the need to reduce the dose until the symptoms subsided may affect the outcome of patients treated with sorafenib.11 Fatigue is usually associated with many endocrine disorders. In cancer patients treated with VEGFR TKI, the overlap of signs and symptoms caused by treatment and the tumor itself makes it difficult to identify and manage endocrine-related dysfunction associated with fatigue development. These factors include changes in the adrenal gland, thyroid gland, and gonads, as are bone and glucose metabolism abnormalities.14,15 Fatigue is one of the most common side effects, and it can also lead to the adjustment of sorafenib dosage or even the interruption of treatment.

Fatigue is one of the common adverse reactions to sorafenib, but few have been reported in patients with advanced hepatocellular carcinoma treated with sorafenib. This study investigated the adverse effects and prognosis of 182 patients taking sorafenib from October 1, 2008, to October 31, 2018, to investigate the effect of sorafenib on the prognosis of such patients.



The clinical data and follow-up results of 182 patients with hepatocellular carcinoma diagnosed at the Affiliated Hospital of Qingdao University from October 1, 2008, to October 31, 2018, were retrospectively analyzed. There were 163 males and 19 females with an average age of 56.03 ± 9.8 years. Clinical data included gender, age, previous treatment (resection, ablation, TACE, others), and adverse reactions (hand-foot syndrome, diarrhea, fatigue), drug dose adjustment, hepatitis, cirrhosis, portal hypertension, alcoholism, diabetes, Child-Pugh classification, TNM staging, survival time, and disease progression time. All patients were diagnosed with hepatocellular carcinoma by postoperative pathology or CT/MR. Solid tumor evaluations were performed in all patients using mRECIST.15

Inclusion criteria: 1. Hepatocellular carcinoma was confirmed by imaging or surgical resection; 2. Sorafenib was administered for more than 3 months.

Exclusion criteria: 1. Patient with Child-Pugh grade C; 2. Patients with an ECOG PS score of ≥3 before medication.

Sorafenib administration

The initial dose of sorafenib was 800 mg/day in two divided doses. Adverse reactions (AE) to administration of sorafenib were recorded, and the criteria for fatigue were based on the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 (NCI-CTCAE v4.0). Adverse reactions were examined on the 10th day and one month after drug administration. When there was an adverse reaction of grade III or above, the dose was adjusted to 400mg/day (one oral dose per day) or temporarily discontinue, and the withdrawal time should not exceed 7 days.16


Patients administered sorafenib were followed up once a month, all in the clinic. Liver function and AFP were reviewed monthly; CT was reviewed once every 3 months, and enhanced CT, enhanced MRI or related examinations (such as radionuclide bone scan or PET-CT) were performed when disease progression was suspected. Time to disease progression was calculated by referencing the date of imaging diagnosis.

Statistical Analyses

Univariate analysis was used to identify predictors of survival using the Kaplan–Meier method, and comparisons were performed using the Log rank test. A p value of <0.05 was considered statistically significant. All analyses were performed using SPSS version 24.0 for Windows (IBM, Armonk, NY, USA).

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