Prevalence and impact of severe fatigue in adolescent and young adult cancer patients in comparison with population-based controls

Compared to adults, a diagnosis of cancer in adolescents and young adults (AYAs) between the ages of 18 and 35 years is rare. Advances in early detection and improvements in cancer treatments have resulted in an overall 5-year survival rate exceeding 80% in AYAs [1]. While AYAs with cancer face challenges similar to adult cancer patients, those in the heart of their youth experience unique cancer-related challenges in addition to usual age-related developmental tasks. The combination of achieving normal developmental milestones and simultaneously coping with a life-changing diagnosis of cancer frequently leads to psychosocial issues among AYAs with cancer [2]. Several studies have documented higher levels of distress and lower quality of life (QoL) in AYAs with cancer in comparison with healthy matched peers or adult cancer patients [3‐5]. Moreover, treatment-related symptoms (e.g., pain and fatigue) and late effects (e.g., second cancers and cardiovascular disease) can interfere with a healthy body image, establishing social relationships, or attaining levels of autonomy and independence. With the expected further gains in overall survival of AYA cancer, it is important to address persistent disease- and treatment-related symptoms that compromise several domains of QoL.

Cancer-related fatigue (CRF) is one of the most common and distressing symptoms reported by adult and childhood cancer patients both during and after cancer treatment [6, 7]. The most commonly used definition for CRF is formulated by the National Comprehensive Cancer Network (NCCN) and defines CRF as “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 that interferes with usual functioning” [8]. The vast majority of studies on the prevalence and severity of CRF have been conducted in adult or childhood cancer patients and only a few studies evaluated fatigue severity in AYAs with cancer. Moreover, the limited AYA-specific studies did not attempt to report on clinically relevant levels of fatigue by using a validated cut-off for severe fatigue [4, 9].

Knowledge on the prevalence of severe fatigue in AYAs with cancer is important, as we know from studies in adult cancer patients that severe fatigue is associated with more functional impairments, lower QoL, and more distress [6, 10]. For AYAs with cancer, the impact of severe fatigue might be even more pronounced because it can interrupt developmental milestones such as completing education, finding first or pursuing employment, beginning a romantic relationship, or starting a family. Understanding factors related to severe fatigue among AYAs with cancer will help health care providers identify who is more likely to experience this symptom. In addition, it will help researchers to determine potential factors that could be addressed in interventions targeting fatigue.

The present study determined the prevalence of clinically relevant levels of fatigue in AYAs with cancer using a validated cut-off for severe fatigue and compared the proportion of severely fatigued cases with the proportion of severely fatigued cases in a sample of gender- and age-matched population-based controls. In addition, the impact of severe fatigue on QoL and potential sociodemographic, treatment-related, and psychological correlates of fatigue severity was explored. A cross-sectional approach was used for this study to gather descriptive information about the presence of clinically relevant levels of fatigue among AYAs with cancer.

In total, 309 letters requesting participation in the study were sent to AYAs with cancer visiting one of the members of the AYA team. The total sample of 89 participants comprised 57% of those who opted in to the study (n = 155) and 29% of all those solicited by mail (n = 309). Six participants were excluded, four since they were diagnosed with cancer under the age of 18 years and two because they were aged above 35 years at diagnosis. Table 1 displays sociodemographic and disease- and treatment-related characteristics of the final sample of 83 AYAs with cancer stratified by the presence of severe fatigue. Mean age at cancer diagnosis for the total sample was 27.3 years (SD 4.4) and mean time since cancer diagnosis was 2.1 years (SD 2.6). The most common diagnosis was testicular cancer (34%) followed by sarcoma (19%). Disease stage at diagnosis was known and applicable in 67 participants. Of those, 36 (54%) were diagnosed with early stage disease (stages I–II) and 31 (46%) with late-stage disease (stages III–IV). The majority of participants had undergone surgery (n = 70, 84%) and chemotherapy (n = 72, 87%) but were not on active cancer treatment at the time of study participation (n = 61, 73.5%). Mean duration of cancer treatment was 15.8 months (SD 20.6). For the subset of 61 patients not on active cancer treatment at the time of study participation, mean duration since completion of treatment was 17.5 months (SD 30.6).

In this study, severe fatigue affected almost half of the AYAs with cancer. The prevalence of severe fatigue in AYAs with cancer was more than twice as high in AYAs with cancer than in gender- and age-matched population-based controls (48 versus 20%). Severe fatigue as assessed with the CIS-fatigue is more prevalent among AYAs with cancer than adult disease-free breast cancer patients 3 years after diagnosis (38%) [19]. The prevalence among AYAs with cancer corresponds more closely with findings from a study performed in adult cancer patients during cancer treatment with palliative intent (47%) [13], which is remarkable given the major difference in prognosis between these two patient groups. In our sample, only a minority of the participants (n = 12, 14.5%) were classified as being treated with palliative intent at the time of participation. Reasons for the high prevalence of severe fatigue in AYAs with cancer have not been studied. One might postulate that, in contrast to adult cancer patients, the higher prevalence of severe fatigue originates from the unique combination of being diagnosed and treated for cancer and the developmental milestones AYAs are confronted with during adolescence and young adulthood.

Alternatively, the higher prevalence of severe fatigue reported by participants in our study could be the result of selection bias. We recruited AYAs with cancer that consulted a multidisciplinary AYA team. The fact that patients consulted a specialized AYA team most likely indicates that these patients had additional disease and/or treatment-related questions or problems, although not all patients had a need for continued and specific care by the AYA team after the first consultation. The percentage of patients having had chemotherapy as part of AYA cancer treatment was high (87%). This further supports the likelihood of selection bias in our sample and might overestimate disease severity of the entire AYA cancer patient population. Nonetheless, we can conclude that within the subset of AYAs with cancer consulting a multidisciplinary AYA team, the prevalence of severe fatigue is substantial.

Significant differences were found in physical, social, psychological, spiritual, and total QoL for severely fatigued AYAs with cancer in comparison with non-severely fatigued patients, which echoes previous studies reporting on the detrimental effects of severe fatigue in adult cancer patients [6, 10]. More psychological distress was a strong correlate of fatigue severity in the present study. In addition, more cancer worrying, female gender, and being unemployed were moderately related to fatigue severity. Geue et al. (2014) studied gender-specific differences in quality of life after AYA cancer and found lower QoL for women than men, including higher levels of fatigue [20]. The finding that more psychological distress and cancer worrying were associated with fatigue severity is in agreement with the impact of fatigue severity on QoL of AYAs with cancer in this study. However, given the cross-sectional design of our study, we cannot draw conclusions on causality. This also limits interpreting the finding that being unemployed was linked to higher fatigue severity, although it may suggest that severely fatigued AYAs with cancer might not be able to find appropriate work. This emphasizes the relevance of further research into this topic.

We only found weak or non-significant links between treatment-related variables and fatigue severity; receiving active treatment at the time of study participation, receiving treatment with palliative intent, and having had radiotherapy were significant but weakly related to fatigue severity. A moderate association was found between late-stage cancer at diagnosis and fatigue severity. In previous studies among adult cancer patients during and after treatment, fatigue appeared to be unrelated to disease-related variables, but the receipt of chemotherapy was associated with fatigue long after treatment [21]. A recently published review among breast cancer survivors after treatment also reported that survivors treated with chemotherapy were at higher risk for developing severe fatigue, as were those survivors with a higher disease stage at diagnosis [22]. As mentioned before, a noteworthy proportion of participants (87%) in our sample had been treated with chemotherapy.

The present study has several limitations. The sample size of our study was relatively small and the low participation rate increases the probability of bias by non-response. Unfortunately, small sample sizes are also seen in other studies in which patients of AYA age are asked to participate [23, 24]. Recruitment for our study took place over a period of 4 years. Additional efforts to increase data collection, such as multiple mailings of questionnaires or follow-up phone calls, were only made in the latter part of the study. Our response rate might have been higher when these efforts were made throughout the entire duration of the study. However, in the AYA HOPE study, fewer than half of the eligible AYAs with cancer responded to questionnaires despite extensive efforts such as multiple mailings, phone calls, and financial incentives [25]. One way to overcome the low response rate in AYA cancer research might be the use of in-person contact and patient-preferred paper-pencil rather than online surveys as recently suggested by Rosenberg et al. [26]. Given the low incidence of cancer in AYAs between the ages of 18 to 35 years, recruitment from multiple institutions in an (inter)national AYA network could also aid the collection of larger samples. This would also increase the ability to generalize findings, which is limited in our study since we recruited patients at a single university medical center. While a broad range of potential correlates of fatigue severity was studied, we cannot rule out the involvement of other potentially relevant factors that have not been examined in this study. For example, sleep problems are strongly correlated with higher levels of fatigue in patients with cancer [27]. In addition, a low level of physical activity and pain are also correlated with cancer-related fatigue [28]. There is evidence that the effect of sleep problems on fatigue is mediated by pain [29]. Unfortunately, we did not include validated instruments to assess sleep problems, physical activity, and pain as potential correlates of fatigue severity in our sample, which is a significant limitation of the study. Notwithstanding these limitations, the present study is the first to apply a clinically relevant cut-off for severe fatigue in AYAs with cancer aged between 18 and 35 years at diagnosis.

In conclusion, given the high prevalence and significant impact of severe fatigue on quality of life of AYAs with cancer, health care providers should pay careful attention to this symptom. In particular, female AYAs with cancer, those with more advanced disease at diagnosis, higher levels of psychological distress, and more cancer worrying seem to experience higher levels of fatigue. The longer-term survivorship rates of AYA cancer illustrate the potential longevity of AYAs with cancer. It is therefore important to investigate the course and persistence of severe fatigue in AYAs with cancer in longitudinal, population-based studies. Such studies would also aid the development of age-specific interventions addressing persistent cancer-related fatigue in AYAs with cancer to enable full participation in society throughout survivorship. Although evidence-based interventions for the management of cancer-related fatigue in adult cancer survivors are available and recommended within guidelines issued by the American Society for Clinical Oncology [30], these interventions have not been tested extensively in AYAs with cancer. Researchers should investigate whether these interventions can also be successfully applied to alleviate persistent cancer-related fatigue, improve QoL, and facilitate participation in society for the understudied population of AYAs with cancer.