IMRT-Induced Acute Fatigue in Patients with Head and Neck Cancer: A Prospective Study

Purpose:

Fatigue profoundly impacts a cancer patient’s quality of life,¹ treatment adherence,² and health care utilization.³  Pre or post radiotherapy (RT) fatigue is a prognostic factor for pathologic tumor response⁴ and survival.^5,6  Patients with head and neck cancer (HNC), who are usually treated with RT because of the structural complexity and functional importance of cancer sites, have particularly high rates of fatigue during treatment.⁷  Most recent research on Intensity-modulated Radiation Therapy (IMRT), a commonly used new radiotherapy that targets tumors with higher doses while avoiding normal structures, has shown that patients experience even higher fatigue compared to conventional-RT.^8,9

The purposes of this study were to 1) describe acute fatigue changes from pre to one-month post IMRT, 2) examine the risk factors for IMRT-induced acute fatigue changes, and 3) explore the relationship between fatigue and other most common treatment-induced symptoms during the acute phase.  

Methods:

This was a prospective study investigating 44 patients with HNC from pre to one-month post IMRT.  Only patients diagnosed with histological proof of squamous cell carcinoma and without distant metastasis were enrolled into the study.  Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 that includes five dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue.  Other common symptoms were collected using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (CTCAE) that categorizes depressive symptoms, sleep problems, cognitive problems, pain, dry mouth, difficulty swallowing, skin burn from radiation, mouth or throat sores, taste change, nausea, vomiting, and sensation of thirst.  Fatigue was also collected by the CTCAE for the purpose of comparing fatigue with other symptoms.  Risk factors (age, gender, race, education, marital status, alcohol and smoking history, BMI, HPV, surgery, chemotherapy, cancer stage, and cancer site) were collected through chart review.  Paired t-test was used to examine fatigue changes from pre to post IMRT.  Regression modeling was used to correlate risk factors with fatigue changes over time.  Correlation coefficients and regression modeling were used to explore the relationship between fatigue and other symptoms.

Results:

All patients received IMRT.  The majority of the patients was male, white, married, and with a history of tobacco use.  Most of them were diagnosed with non-laryngeal cancer, had stage IV cancer, received current chemoradiotherapy, and had feeding tubes.  Among patients with oropharyngeal cancer (a total of 17), 88% of them were either HPV or P16 positive, and all of them received concurrent chemoradiotherapy.

Patients’ overall fatigue increased significantly from pre (47 ± 16) to one-month post (60 ± 16) IMRT (t=5.27, p=0.000).  Of all the patients, 40% experienced severe fatigue (MFI ≥ 65) at one-month post IMRT, while only 10% had severe fatigue at pre IMRT.  Additionally, all five dimensions of fatigue increased statistically significantly in the following order from the highest to the lowest: physical fatigue, reduced activity, general fatigue, reduced motivation, and mental fatigue.

Multivariate analysis revealed that chemotherapy and pre-IMRT fatigue were significantly correlated with fatigue changes over time (F=10.89, p=0.000).  The patients receiving chemotherapy experienced increased fatigue changes from pre to one-month post IMRT (t=2.29, p=0.027).  Interestingly, patients with lower pre-IMRT fatigue were more likely to have increased fatigue change over time, compared with patients with higher pre-IMRT fatigue (t=-3.56, p=0.001).

Fatigue was the third severest symptom among the 13 common symptoms at pre-IMRT in our sample (the first two were sleep problems and pain), and the second severest symptom at one-month post IMRT (the first was taste changes).  Fatigue at either pre or post-IMRT was significantly correlated with other biobehavioral symptoms, including depressive symptoms, sleep problems, and cognitive problems at either or both time points.  Pre IMRT fatigue explained the most variance (20%) in a previously identified HNC specific symptom cluster,¹⁰ involving symptom of pain, dry mouth, difficulty swallowing, skin burn from radiation, mouth or throat sores (mucositis) and taste change, after controlling other variables, such as sleep problems and chemotherapy (F=9.22, p=0.000). 

Discussion:

Patients with HNC reported remarkably increased fatigue at one-month post IMRT, compared to pre IMRT, and 40% of them experienced severe fatigue (MFI ≥ 65).  It appears that different dimensions of fatigue were affected by the treatment in different severity levels.  The fatigue dimensions related to physical function and activity were more significantly influenced by the treatment than the dimensions related to motivation and metal function.  This finding may guide future studies to pay attention to different dimensions of fatigue.

Consistent with previous studies,^11,12 chemotherapy is a significant risk factor for fatigue.  Our study further showed that patients receiving current chemoradiotherapy experienced significantly higher increased fatigue at one-month post IMRT than patients receiving only radiotherapy or radiotherapy plus surgery.  This finding indicates the negative synergistic effect of multiple concurrent treatment modalities on fatigue.  Interestingly, patients with lower pre IMRT fatigue experienced much more significant increases in fatigue from pre to one-month post IMRT than those with higher pre IMRT fatigue did.  The reason for this is unclear, and future larger studies are warranted.  

By comparing fatigue with other most common treatment-induced symptoms for patients with HNC, our study demonstrated that fatigue was the only symptom that was consistently among the top three severest symptoms experienced by patients at both pre and post IMRT.  Furthermore, pre IMRT fatigue was the most predictive variable for the HNC specific symptom cluster, involving the most common radiation-induced symptoms in this population.

Conclusion:

Fatigue is one of the major treatment-related symptoms experienced by patients with HNC.  HNC patients receiving IMRT report significantly increased acute fatigue from pre to one-month post IMRT.  Concurrent chemotherapy further worsens the symptom of fatigue.  Fatigue, in turn, is the most significant risk factor for other common radiation-induced symptoms, or the HNC specific symptom cluster.  Although these findings are from a prospective longitudinal study design, further larger studies are needed to verify our results.  Additionally, as there is no Food and Drug Administration (FDA)-approved pharmacological agent that reliably prevents or treats fatigue,¹³ future research on understanding the molecular and genetic mechanisms of fatigue is critical to its successful management.