As the utilization of OAAs for cancer management continues to rise, understanding OAA treatment tolerability in older adults is imperative to the development of personalized OAA treatment plans and symptom monitoring strategies for this population [16]. Our retrospective secondary analysis of combined EHR data with patient-reported outcome data provided insights into side-effect experiences and treatment changes affecting older adult cancer patients taking capecitabine. They were more likely to experience certain severe side effects such as fatigue and hand-food syndromes than younger adults and tended to be more likely to have dose reductions and interruptions. With our primary focus on the experiences of older adults, we also identified other potential factors associated with the severity of side effects of capecitabine and capecitabine dose reduction and dose interruption during the study period, such as the days on the treatment, the number of outpatient medications, capecitabine treatment type, and initial dosage.
It is not surprising that participants in the two samples (EHR and patient-reported outcome study) differed in regard to their clinical characteristics. Between the two data sets, there was a heterogeneous sample with regard to cancer diagnoses. The patient-reported outcome sample only included gastrointestinal (GI) cancer patients, while the EHR sample included patients diagnosed with breast cancer. It was expected that the combined dataset would cover all cancer types that capecitabine has been indicated for. The complement of the EHR sample increased the overall sample size and balanced the combined set to be more likely to represent the patient population taking capecitabine in clinical practice. As noted, the comparison of side effects experienced by two samples revealed that patients from the patient-reported outcome study were more likely to report severe diarrhea, constipation, fatigue, and sleep difficulties. It seems to be reasonable that the GI cancer-only group experienced more frequent and more severe diarrhea and constipation. To interpret the result that EHR samples experienced significantly less frequent and less severe fatigue and sleep difficulties, the potential explanation is patients may less likely to report their subjective symptoms, such as fatigue, to clinicians during clinical visits [17], or less likely to be documented in the EHR notes even when the patients mentioned their experiences of these two side effects [18]. Previous studies indicate that clinicians are likely to underestimate the severity of the subjective symptoms and sometimes overlook the patient’s self-report [19, 20].
The identified common side effects of capecitabine from clinical notes were similar to those self-reported by patients in the pilot study and those in the SIDER database [13], including fatigue, diarrhea, nausea, constipation, HFS, sleep difficulties, mouth sores, and vomiting. Compared to the frequencies of common side effects capecitabine reported in the literature, our patient sample experienced higher incidences of fatigue (69% vs 42%), constipation (35% vs 14%), and sleep difficulties (25% vs 7%), and lower incidences of HFS (30% vs 54%) [13]. Patients sampled from routine care (documented in EHR clinical notes) may have a different level of side effect experiences compared to those in clinical trials as they often have strict inclusion and exclusion criteria for participation which may affect the documented occurrence of side effects [18, 21]. Regarding the lower incidence of HFS identified in our sample, as HFS is a well-known common and significant side effect of capecitabine, clinicians may have adopted certain strategies to control the development of HFS in clinical practice, such as more intensive assessment and management of early signs and symptoms of HFS, e.g., having dose reductions or dose on-held [22, 23], as indicated in this analysis that the severity of HFS was significantly associated with dose reduction.
As expected, age was found to be associated with the severity of several side effects of capecitabine [24]. Specifically, this study found that older adults were more likely to experience fatigue than younger adults and they also experienced more severe fatigue and HFS. Fatigue is one of the most prevalent cancer treatment-induced side effects [25], and older adult patients are often more susceptible to fatigue due to declined physical function [26]. About 40% of older adults reported moderate-severe fatigue in this study. The number is higher than what a previous study has reported that 25% of patients rated their fatigue as moderate-severe when taking oral chemotherapy [27]. While 7% of older adults rated their HFS as severe or extremely severe in the current study, this was less than 21% older adults reported in a previous randomized controlled trial [28], and 11% of older adults aged older than 70 years reported in a chart review study [29]. Such differences may be because the sample size of the current study was small, and the sample of participants aged 65 years and above was limited. Both fatigue and HFS are OAA-related common side effects and are difficult to manage, especially in elderly patients, which can significantly impact their quality of life and may cause impairment of function [30]. This study demonstrated that older adults were particularly vulnerable to severe fatigue and HFS of capecitabine treatment even when having other socio-demographic and clinical factors controlled in the models (see Table 3). Therefore, it is important to assess OAA treatment tolerability in a timely fashion and monitor for early signs and symptoms of toxicities for older adults in order to intervene early to prevent the development of severe side effects [16].
The current literature implies that the severity of side effects of OAAs may positively correlate with the number of outpatient medications and the number of comorbidities [9]. Concurrent medications may contribute to patients’ experiences of severe side effects of OAAs due to drug interactions or combined drug effects. It is not surprising that this study found that the number of outpatient medications was significantly associated with patients’ experience of more severe fatigue of capecitabine. Older adults in this study were found to be taking significantly more outpatient medications than younger adults, correspondingly, they presented with more fatigue. Surprisingly, older adults in this study had a smaller number of comorbidities than younger adults, which may be because of an incomplete list of comorbidities in older adults’ medication records. This may explain why there was not an association between the number of comorbidities and severe fatigue or HFS. As one of the limitations, the study did not track the specific type of comorbidities and type of concurrent medications, thus it is unclear whether specific types of comorbidities or medications may significantly interfere with older adults’ tolerance to OAA treatment, which can be further explored in future studies.
Co-occurring symptoms are common in patients receiving chemotherapy [31]. Interestingly, this study revealed different patterns of co-occurring side effects of capecitabine between older and younger adults. While the severity of many side effects was found to be correlated with each other among younger adults, this was not the case in the older adult sample. For example, the severity of nausea and vomiting in younger adults was highly correlated, however, the severity of nausea in older adults was not significantly correlated with their vomiting. This may be because older adult patients often have a lower risk of chemotherapy-induced nausea and vomiting than younger adults [32]. HFS is another unique example, where there were significant correlations in the older population but not the younger sample. By contrast, diarrhea did not present any correlations with other side effects in older adults but was significantly correlated in the younger population. These different symptom cluster patterns between younger and older adults have not been reported in the literature before. As the finding of co-occurring side effects of OAA can be useful in guiding targeted side effect management interventions for older adults in the future, this finding may need to be further validated by more studies with large sample size, particularly, since the severity of all side effects in this study tended to be low in general.
Dose reductions and temporary dose interruptions may be used as clinical strategies for OAA-related toxicities management [33]. While initial dose reductions are often related to age, this study indicated that older adults tended to be more likely to experience dose reductions and treatment interruptions than younger adults during capecitabine treatment courses, however, such differences were not statistically significant. The limited sample size can be one of the potential explanations for the non-significance. One previous study of patients receiving infusion chemotherapies (oxaliplatin plus fluoropyrimidines) instead of oral chemotherapy (capecitabine) [34] reported significantly more elderly patients compared to younger participants experiencing dose reductions and treatment interruptions. Current literature suggests that elderly patients have higher risks for dose reductions while taking capecitabine [35]. One study focused on capecitabine monotherapy for colorectal cancer has reported that dose reductions and dose interruptions occurred in 17–24% of patients who experienced HFS [7]. This seems to be aligned with our results that the severity of HFS was significantly associated with dose reductions. However, the severity of HFS was not significantly associated with dose interruptions, although patients with dose interruptions tended to have more severe HFS.
Dose reduction was associated with a few demographic and clinical characteristics in this study. For example, those with breast cancer were more likely to have dose reductions than other types of cancers, which may explain why females were found to be more likely to have dose reductions than males. One previous study observed greater capecitabine side-effect severity in female patients [36]. Females might have experienced some severe side effects that led to their dose reduction. Finally, since capecitabine dose reductions can be a toxicity management strategy, it may explain why patients on capecitabine monotherapy were more likely to experience dose reductions than those on the combination of capecitabine with other chemotherapy.