Burden of symptoms associated with development of metastatic bone disease in patients with breast cancer

Numerous studies have reported symptom trajectories in patients with breast and other cancers relative to specific events such as initial diagnosis, surgery, chemotherapy, and death [10, 20‐28]. The present study contributes to the understanding of symptom trajectory in the context of the onset and diagnosis of bone metastatic disease, showing that both the severity of symptoms as well as the proportion of patients experiencing moderate to severe symptoms began to increase for several months prior to the actual diagnosis of bone metastases. In particular, the risk of developing moderate or severe fatigue, pain, and numbness/tingling increased significantly in the months leading up to the diagnosis. The clinical implications of these findings are that oncologists should be aware that increasing symptoms in patients with advanced breast cancer may predict or reflect the onset of bone metastases. Earlier detection and treatment of bone metastases has the potential to reduce the increase of pain as well as to prevent skeletal events and loss of mobility incurred from bone destruction when bone metastases are discovered at a later stage.

Notably, after the diagnosis of bone metastases, the burden of fatigue, pain, and anxiety appeared to decrease or flatten, likely reflecting the effects of more aggressive patient management [6] which included introduction or intensification of pain medication, as well as the use of bone-targeted agents. A large longitudinal study in a mixed cancer population also reported a relatively flat burden of pain, nausea, anxiety, and depression in the 6 months before death, and the authors suggested that these symptoms are those for which medication strategies exist, although they were unable to evaluate treatment [27]. Alternatively, the decrease in PCM scores after bone metastases diagnosis in our study might have been influenced by the effect of missing data due to patient attrition and/or might reflect patient adjustment to progressive disease.

The potential effects of increased patient management following diagnosis were also reflected in the Kaplan-Meier curves for all of the symptoms (except for loss of interest in others, a measure of depression), which showed a change in trend at 30 days after onset of bone metastases, with acceleration leading into the 30-day point and subsequent deceleration. The cumulative proportion of patients with moderate to severe symptoms increased over time for most symptoms, particularly for pain and fatigue which affected a majority of patients within 3 months of the onset of bone metastases. Trouble sleeping and numbness/tingling had slower onsets, but also affected a majority of patients at a moderate to severe intensity within 1 year after the onset. Anxiety and loss of interest in others developed in smaller proportions of patients, with a slower course than the other symptoms.

Previous studies of longitudinal symptom burden in our selected population, breast cancer patients with bone metastases, have reported increases of symptom burden over time, but either examined symptom burden as a composite [12], rather than individual symptoms, or focused on predictors of increased symptoms [13]. The study most similar to ours evaluated symptom trajectory in the 6 months before death in a mixed cancer population using the Edmonton Symptom Assessment System [27]. These authors demonstrated that fatigue, appetite, well-being, and drowsiness increased steadily in severity leading up to death, while pain, shortness of breath, anxiety, depression, and nausea remained relatively flat during this time period. In our study, we selected the group of symptoms identified in the ECOG SOAPP study as the most prevalent moderate to severe symptoms [7] in patients with breast cancer (fatigue/tiredness, disturbed sleep, pain, dry mouth, distress, numbness/tingling, and sadness) for which there were corresponding PCM items: fatigue, trouble sleeping, pain, anxious (as a measure of distress), numbness/tingling, and loss of interest in others (as a measure depression [18]). In addition to the differences in individual symptoms selected for analysis in our study relative to previous studies, our results offer a unique perspective on the trajectory of symptoms owing to the anchoring of our analysis to the onset and diagnosis bone metastases.

Despite the decrease in pain after diagnosis of bone metastases, a substantial increase in analgesic use after bone metastases diagnosis was not observed in the present study, with just 16 % of patients having new or increased pain medication after diagnosis. A major limitation to this dataset is that analgesic medication may have been provided by clinicians outside of the oncology practice. The proportion of patients in this study receiving opioid medications in the period leading up to diagnosis of bone metastases was approximately 10 %. This percentage is similar, although slightly lower, than the percentages of strong opioid use reported in an observational study evaluating the prescription of analgesics in patients with solid tumors (13 %) [29] and for patients with breast cancer and bone disease enrolled in a phase 3 clinical trial (16 %) [30].

The decrease in pain observed after the diagnosis of bone metastases may be associated with the use of bone-targeted agents and/or external beam radiation to manage pain without use of opioid analgesics [2, 4, 30, 31]. Nearly half of the patients were receiving bone-targeted agents and these agents were prescribed rapidly following the diagnosis of bone metastases. We note that the data for bone-targeted agents are far more robust than for pain medication, as the former medications were administered in the oncologist’s office and were therefore far more likely to be recorded. The observation that half of the patients did not receive any treatment with bone-targeted agents points to an opportunity to further improve management of bone metastases in this population.

A unique aspect of this dataset was that patient-reported outcomes were captured as part of routine assessment in the clinical practice setting, thereby allowing symptom burden to be studied over time relative to the diagnosis of bone metastases in the absence of a clinical trial. In addition, many patients included in this study would otherwise have been excluded from a prospective clinical trial due to low ECOG performance scores and/or limited life expectancy. Our study describes real-world findings in a population of over 1000 women treated in clinical practice across the USA that is representative of women treated in the community setting and therefore more generalizable to the broader breast cancer population of the USA than the population studied in clinical trials. Of note, the median time to diagnosis of bone metastases was 20 months in this population (in which half of the patients had stage IV disease), shorter than that recently reported for patients with local (stages 0–II) or regional disease (stage III) (30 and 33 months, respectively) [32].

A strength of our study was the use of electronic medical records; however, electronic datasets in the clinical practice setting may also present some limitations as their use is still evolving and validation studies of the sensitivity and specificity of diagnostic and treatment data are needed. Importantly, these data reflect only diagnoses and treatments provided in the oncology clinic from community-based practices. Although close to 90 % of community-based oncology/hematology practices today have adopted electronic medical records for the routine care of patients [33], during the study period, the adoption of electronic health records was lower and therefore our study may differ in practice patterns and patient characteristics from the general US patient population. The identification of patients with bone metastases reliant on ICD-9 code in the OSCER database might be a source of misclassification and selection bias; selection bias is also possible from the inclusion criterion requiring at least one PCM assessment. Furthermore, analyses of pain medication use were limited by missing data. Drugs that are administered outside of the oncology clinic including oral medications and infusions) may not be recorded in the patient health record. These missing data are particularly important to the analyses of pain medication, as a majority are oral and many can be purchased over the counter at retail pharmacies. Therefore, we cannot exclude the possibility of underestimation of the pain medication use in this study, which may translate into the underestimation of the pain burden associated with the development of bone metastases in breast cancer patients. There are also other medications that could affect pain in cancer patients with bone metastases, such as bone-targeted agents, corticosteroids, and anticonvulsants, which may have confounded pain estimation. An additional limitation to this study is that site selection was not based on a random process since the data housed in OSCER with corresponding PCM data were limited to the Vector Oncology data from selected hematology/oncology practices.

In conclusion, we observed increasing symptom burden, particularly for pain and fatigue, both before and after the diagnosis of bone metastases in women with breast cancer in this retrospective patient record study conducted in the USA. These findings reinforce the need for symptoms to be proactively monitored and managed by health care providers. Advanced detection and treatment of bone metastases could reduce symptom burden and prevent further decline in HRQoL.