Abstract
Background: Radiation therapy (RT) has been widely used for palliation in multiple myeloma. However, no data exist on symptom assessment and patient-reported outcomes regarding the efficacy of RT in this disease process. This study aims to demonstrate the impact of palliative RT on patient-reported symptoms in patients with multiple myeloma.
Materials and Methods: Our Radiation Oncology and Supportive Care Medicine clinics established the use of a modified Edmonton Symptom Assessment Scale (ESAS) in 2015 assessing 12 symptom domains. All had ESAS data available from each encounter. Demographic and clinical data were retrospectively collected from an institutional data warehouse. We examined total and component survey scores for correlated data of patients during radiation treatment and patients not treated with radiation.
Results: Clinic records of 30 patients with multiple myeloma seen in the Radiation Oncology and Supportive Care clinics from 2015 to 2018 were retrieved. A total of 91 discrete surveys were collected (1183 data points). Twenty of these were collected from weekly visits from 12 patients receiving RT; the remainder were from new patient or follow up encounters. Odds ratios were lower with radiation therapy for total scores (OR 4.86, p = .007), as well as several component scores.
Conclusions: The use of palliative RT was associated with 5 times lower total symptom scores compared with nonuse. Similar beneficial results were found for several component scores. These patient-reported outcomes strongly suggest that providers should consider palliative radiation for symptomatic multiple myeloma patients. These data should be prospectively validated in a larger cohort of myeloma patients.
Introduction
There is increasing recognition of the value of collecting patient-reported symptoms and outcomes in cancer care. Standard EMR (electronic medical record) data points rarely capture the full extent of patient symptomology. Patient-reported assessment of symptoms related to their diagnoses or toxicities from treatment may or may not coincide with physicians’ ratings, depending on the assessment tools used and the clinical scenario [Citation1–4]. Some studies have shown that reduced toxicities from treatment also translate into improved quality of life as perceived by patients [Citation5]. These data are important in counseling patients on expected symptoms related to their disease processes and recommended treatments, and to help determine appropriate measures to alleviate symptoms. Randomized clinical trial data have demonstrated an improvement in overall survival by more than 5 months in patients with metastatic solid tumors by actively incorporating patient-reported outcome (PRO) data into clinical workflows [Citation6].
The Edmonton Symptom Assessment Scale (ESAS) is a PRO tool that was developed and has been validated in the palliative care setting [Citation7–9]. A modified version of the tool was developed for use in the cancer care setting and has been implemented in many institutions for routine use [Citation10]. The modified ESAS tool also correlates with other symptom assessment scales but is easier to use [Citation11]. Prior data from our institution showed that the ESAS-r-CSS scale (ESAS-revised-constipation, sleep disturbance, spiritual wellbeing) has benefit in describing symptom clusters in unselected radiation oncology patients [Citation12].
Despite the availabilities of novel therapies and improvement in outcomes, multiple myeloma (MM) remains largely incurable and health-related quality of life (HRQL) considerations are of particular interest. Patients with multiple myeloma tend to have a high symptom burden which translates into a worse quality of life [Citation1] and lower physical functioning, especially in older patients [Citation13]. These symptoms and/or side effects of treatment may be underreported to the health care team, but many of these symptoms may be managed with appropriate palliative care [Citation14]. Systemic therapy for myeloma may improve some of the disease-related symptoms but sometimes at the cost of toxicities, which can increase symptom burden [Citation15]. The role of palliative radiation therapy (RT) in alleviating subjective symptom burden in patients with multiple myeloma (MM) has not been previously studied, despite widespread use of RT in MM. This retrospective study aims to demonstrate whether symptom burden is reduced in patients with multiple myeloma receiving palliative RT.
Material and methods
A modified ESAS tool (ESAS-r-css) was implemented in 2015. The ESAS-r-css consists of twelve symptom domains rated from 0 to 10: pain, tiredness, drowsiness, nausea, appetite, shortness of breath, depression, anxiety, overall wellbeing, spiritual wellbeing, difficulty sleeping, and constipation; the thirteenth domain is the total score. A score of zero indicates the absence of symptoms, whereas a score of 10 indicates severe, uncontrolled symptoms. Patients completed these forms (either on paper initially, or electronically in later years) at each consultation and follow up, as well as at each weekly on-treatment visit for patients undergoing radiation treatment. Scores above 5 were addressed with the patients by nurses or clinicians, and intervention offered as appropriate (counseling, pain management, etc). All patients in this study had ESAS data available which were collected at the beginning of each encounter in the RO (radiation oncology) and SCM (supportive care medicine) clinics. Approval for this retrospective review was obtained from the Moffitt Cancer Center Institutional Review Board. Total and component survey scores were recorded for all patients who did or did not receive RT. Demographic and clinical data, including transplant status, disease status (complete remission, partial response, stable disease, progressive disease), number of lines of treatment delivered, steroid use, hemoglobin levels, narcotic use, and recent hospitalizations, as well as radiation data, were retrospectively collected an institutional data warehouse. Data were de-identified prior to analysis.
Ordinal regression analysis was used, utilizing a GEE repeated measures modeling approach in SAS with Proc Genmod. The difference between treatment and no treatment was utilized as the independent variable. The odds ratio for the ordinal outcome for lower (improved) scores associated with a treated period is examined. A significance level of .05 was chosen for this analysis. Multiple encounters on the same day as well as multiple data collections from the same patient over time are accounted for in this analysis using the GEE repeated measures modeling approach including a time effect for time from diagnosis of the encounter.
Results
Thirty-two patients were extracted from the ESAS database with a multiple myeloma diagnosis seen in the radiation oncology and supportive care medicine clinics between 1 June 2015 and 31 May 2018. Two patients were miscoded (wrong diagnosis) leaving 30 patients for the final analysis (female N = 17; male N = 13). Twelve of the 30 patients were referred from the malignant hematology clinic and received or were receiving palliative radiation therapy. Fourteen patients had undergone stem cell transplant prior to the first ESAS collection. Patient characteristics are listed in .
Table 1. Patient characteristics of patients receiving and not receiving palliative radiation.
Ninety-one (N = 91) discrete ESAS forms were collected translating to 1183 data points. There were no missing data points, likely owing to a medical assistant or nurse reviewing forms with patients immediately to screen for high scores. Twenty forms (N = 260 data points) were from weekly treatment visits (patients are seen once weekly immediately after their treatment time, after a variable number of delivered radiation treatments) for patients currently undergoing palliative radiation; the remainder were from new patient visits or from follow up encounters in either clinic (i.e., follow-ups after completion of radiation therapy or follow ups after initial consultation in SCM clinic). Most patients treated with radiation did not have a follow-up encounter in the radiation clinic unless they required additional radiation to a different site, and therefore did not have additional ESAS data beyond the radiation treatment period. Median radiation dose delivered was 20 Gy (range 8-30 Gy) in 10 fractions (range 1–12 fractions). Two of 12 patients reported fatigue during weekly on-treatment visits; the remainder reported no acute toxicities.
Univariate analysis of ESAS components revealed favorable outcomes with radiation therapy for total scores, pain, shortness of breath, depression, anxiety, overall wellbeing, spiritual wellbeing, and constipation (see ). Patients who completed or who were currently receiving palliative radiation therapy demonstrated five times lower total scores compared with patients not receiving palliative RT (p = .001).
Table 2. Odds ratio of total and component survey scores for patients with multiple myeloma receiving palliative radiation therapy.
Receipt of radiation therapy remained significant on multivariable analysis, with a few exceptions: RT did not remain significant for pain scores when adjusting for disease and hemoglobin; for overall wellbeing when adjusting for race; and constipation when adjusting for the number of lines of prior therapy. Age, race, disease status, time from diagnosis, hemoglobin levels, number of lines of treatment, and recent hospitalization were found on multivariable analysis (see ) to correlate with ESAS scores on multiple domains. Only the components which were found significant for treatment in the initial univariable analysis were included in multivariable analysis. Advanced age was associated with lower total ESAS scores, as well as lower scores on pain, shortness of breath, depression, anxiety, and constipation. Higher ESAS scores were seen in nonwhite patients across multiple components. Patients who were at an extended time from diagnosis had worse scores for pain, depression, anxiety, overall wellbeing, and total scores. Similar results were seen in patients who had been treated with multiple lines of systemic therapy. Hospitalization within the prior 30 days correlated with lower scores across multiple ESAS domains.
Table 3. Odds ratios (95% confidence intervals) for covariates.
Discussion
The role of radiation therapy as assessed by PROs has not been previously examined in patients with multiple myeloma. Our data suggest that palliative radiation therapy may significant positive impact on distress and/or symptom scores in patients with multiple myeloma. Patients in this study were referred for radiation for pain, cord compression, or pathologic fractures. Benefits were seen in patient-reported pain levels, which is not unexpected, but also in terms of constipation, shortness of breath, anxiety, depression, wellbeing, and total scores. Constipation may have been alleviated due to decreasing narcotic analgesic requirement, although this could not be formally measured due to insufficient documentation, as well as less likely radiation-induced loose stools or diarrhea from treatment of the pelvic regions. Decreasing pain may also contribute to decreased anxiety, depression, and overall and spiritual wellbeing. The median radiation dose in this study was 20 Gy in 10 fractions. There are usually minimal toxicities associated with these doses, regardless of the treatment site. In the acute period (during treatment), no side effects other than fatigue were reported, although longer term follow up of potential toxicities is not available. Thus, given the reduction in symptom burden in those receiving palliative radiation, the benefits are likely to outweigh the harms of radiation therapy in this population.
Patient-reported outcome scales can be valuable tools in the clinic to objectively evaluate the impact of interventions on specific domains from a patient perspective. This perspective is especially critical in oncology where interventions may be expensive, toxic, or of limited value to the patient despite statistical improvements in patient survival outcomes. PROs can help guide providers toward more effective interventions. In fact, an improvement in survival has been demonstrated with the use of PRO-based interventions alone compared with usual care in patients with metastatic solid tumors [Citation6].
Multivariable analysis shows certain demographic features are associated with higher or lower ESAS scores. Age, hemoglobin, and recent hospitalization were associated with lower (better) ESAS scores. On the other hand, race, increasing number of prior systemic treatments, and increasing time from diagnosis were associated with higher (worse) ESAS scores, the latter of which is also supported by the literature [Citation16]. Older patients in this series had lower scores, despite typically having more comorbid conditions and historically having higher symptom burdens in oncology literature [Citation17]. Higher hemoglobin levels may be associated with improved energy, leading to enhanced wellbeing [Citation18]. Patients who are hospitalized within the prior 30 days for treatment or treatment-related toxicities may have had palliative care interventions, radiation oncology consultations, optimization of pain medication regimens, IV fluids, and other interventions; they may also have a more clearly defined plan of care for the immediate future which can help alleviate short term uncertainty and anxiety. It also stands to reason that increasing time from diagnosis and requirement for additional treatment lines is associated with increasing symptom burden. Multiple studies have demonstrated disparities in cancer outcomes among nonwhite patients [Citation19–22] and this is suggested here. Further investigation of this is warranted in this setting as well.
There are some limitations to our study. The indications for referral to supportive care clinics were not evaluated, whereas for radiation indications were pain, cord compression, or prophylaxis against fracture or cord impingement. As a result, the baseline symptomology could be vastly different between the groups. Patients were not randomized to receive radiation or not; therefore, there may be other, unmeasured differences between groups that contributed to differences in symptomatology. Not all physical symptoms can be addressed by radiation; for example, chemotherapy-induced neuropathic pain, chronic fatigue, and other symptoms related to MM or its treatment are not ‘targetable’ with radiotherapy. Not all domains on the ESAS form can be directly addressed with palliative radiation, although as noted there likely exists an indirect benefit. The ESAS form also does not specifically address radiation-related toxicities and as alluded to earlier, it cannot be determined whether symptom reduction is directly attributable to palliative radiation. High scores were reviewed by the clinical staff and may have been addressed with other measures, such as pain medications, counseling, or other interventions and therefore may have contributed to lower eventual scores. ESAS data is not yet available in our malignant hematology clinics, so it is unclear how scores would compare in those clinics for patients limited to systemic interventions. The majority of patients did not have additional ESAS data beyond the treatment period, and therefore the full effect of radiation may not have been realized yet. We also have limited patient numbers in this specific cohort: as a tertiary referral center, patients often travel from extended distances for hematology interventions and those who are recommended palliative radiation may opt to receive treatment closer to home. Furthermore, the patients in this cohort who did not receive radiation were largely followed by the supportive care clinics, whose scores may as a result be lower in general. Therefore, the true impact of palliative radiation may in fact be overestimated in this cohort.
To further evaluate the impact of specific interventions on patient-reported outcomes, ESAS data should be collected prospectively from malignant hematology clinics from time of diagnosis and throughout a patient’s treatment journey to determine which domains are truly impacted by specific interventions. Then, the specific reasons for referral to the radiation oncology and supportive care medicine clinics should be prospectively determined to better evaluate the impact of radiation vs. other interventions on patient symptom burden over other supportive care interventions. The impact of radiation therapy may be further defined by collecting data at pre-specified time points before, during, and after radiation therapy and at specific follow up intervals. Prospective collection of patient-reported toxicities would also help elucidate benefits vs. harms of interventions.
In conclusion, palliative radiation therapy is associated with a significant impact on patient symptom burden as measured by the ESAS not only directly in terms of pain, but also indirectly in terms of non-tangible domains such as anxiety, depression, and overall well-being. This suggests that referrals to radiation oncology for palliative purposes should be more readily considered given the low cost, low toxicity, high-value impact on patient care.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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