The role of radiation therapy in palliative care of children with advanced cancer: Clinical outcomes and patterns of care

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1 Received: 27 July 2016 Revised: 1 September 2016 Accepted: 9 September 2016 DOI: /pbc RESEARCH ARTICLE Pediatric Blood & Cancer The American Society of Pediatric Hematology/Oncology The role of radiation therapy in palliative care of children with advanced cancer: Clinical outcomes and patterns of care Sumeeta Varma 1 Debra L. Friedman 2 Mark J. Stavas 1 1 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee 2 Division of Pediatric Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee Correspondence Sumeeta Varma, Department of Radiation Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building, Ste B-1003, Nashville, TN sumeeta.varma@vanderbilt.edu Abstract Background: There are few published data to guide the use and timing of palliative radiation therapy (RT) in children. We aimed to determine the clinical outcomes of palliative RT in children and the relationship with palliative care and hospice referrals. Procedure: A retrospective chart review was performed on all patients younger than 18 years who received palliative RT in our clinic from January 2005 to January Results: In the specified time period, 50 children underwent 83 courses of palliative RT. Median survival after treatment was 124 days (range, days). Fifteen courses were delivered to children in the last 30 days of life (dol). Palliative RT was successful in 89% of courses delivered before the last 30 dol versus 28% of courses delivered in the last 30 dol (p < , Fisher s exact test). At the time of data collection, 43 children were deceased. Altogether, 88% of children who received palliative RT were also referred to our institution s pediatric palliative care team or to hospice at some time in their course. Of the children who died, 74% were referred to hospice and 34% were on hospice while receiving palliative RT. For children not already on hospice, the median time to hospice referral was 96 days after the last fraction (range, days). Conclusions: Palliative RT is effective in children with advanced cancer, although less so in the last 30 dol. With careful care coordination and multidisciplinary collaboration, RT can be successfully integrated into supportive and end-of-life care for children with advanced cancer. KEYWORDS end of life, hospice, palliative care, patterns of care, radiation oncology, radiotherapy 1 INTRODUCTION Radiation therapy (RT) is a well-established modality for palliation of symptoms from metastatic and locally advanced cancer. For adult patients, there is a sizable body of literature, including prospective randomized clinical trials and evidence-based clinical guidelines, regarding the epidemiology and effectiveness of various radiotherapy approaches for palliation of bone pain, 1,2 symptomatic brain metastases, 3 5 spinal cord compression, 6 8 and other symptoms. However, the indications and outcomes after palliative radiation in pediatric patients remain underreported. Several small single institutional studies have demonstrated improved symptoms burden with radiation However, the optimal timing, delivery, and role of palliative radiation in the continuum of end-of-life care remain unknown. Here we explore the use of palliative radiation in advanced pediatric malignancies with Abbreviations: RT, radiation therapy; dol, days of life a focus on the timing of radiation during the disease course relative to palliative care and hospice referrals. 2 METHODS A retrospective chart review was performed on all patients younger than 18 years who received palliative radiation therapy at Vanderbilt University Medical Center between January 2005 and January Treatment courses were classified as palliative, rather than definitive, in intent if they were so designated by the treating radiation oncologist in treatment planning or consultation notes. If treatment intent was not explicitly stated in the available documents, it was assigned based on a comprehensive review of the chart by a designated investigator (S.V.). In general, RT was considered to be palliative in children with advanced cancer who were ineligible for or whose disease had persisted/progressed through standard of care first-line therapy, and Pediatr Blood Cancer 2017; 64: e26359 wileyonlinelibrary.com/journal/pbc c 2016 Wiley Periodicals, Inc. 1of7

2 2of7 VARMA ET AL. in whom the goal of RT was amelioration or prevention of a specific symptom. In most cases, patients had in fact undergone multiple unsuccessful lines of systemic, cure-directed therapy. Data were abstracted from patient charts and managed using REDCap electronic data capture tools hosted at Vanderbilt University. 12 The study was reviewed and approved by the Institutional Review Board of Vanderbilt University. For each patient, patient gender, tumor histology, time of death or last follow-up after palliative RT, whether and when palliative care and hospice referrals were placed, and for deceased patients, the location of death (hospital vs. home vs. inpatient hospice) were recorded. For each palliative radiation course, data recorded included patient age, site treated, presenting symptom for palliation, radiation dose, number of fractions, elapsed treatment days, whether the course was completed as prescribed, and symptom response. Symptom response was determined by review of clinic and inpatient notes from the end of RT to death or last follow-up. Symptoms were considered to have responded if any provider documented any of the following: (1) patient or parent report of subjective improvement in the symptom, (2) improvement in relevant physical examination parameters such as work of breathing or abdominal distension, or (3) decrease in medical treatment required for the symptom such as pain medication or supplemental oxygen. Statistical analysis was performed using Microsoft Excel (ver ). Relationships between treatment variables and palliative outcomes were evaluated using Fisher s exact test. The threshold for statistical significance was set at a two-tailed p value < RESULTS In the specified time period, 50 pediatric patients underwent 83 courses of palliative RT: 37 patients underwent a single palliative RT course, 4 patients underwent 2 courses, and 9 patients underwent 3 or more courses. Patient characteristics and indications for palliative RT are summarized in Table 1. The median age at the time of RT was 10.3 years (range, 2 months to 18 years). The most common histologies treated were neuroblastoma (23%), rhabdomyosarcoma (18%), Ewing s sarcoma (9.6%), and osteosarcoma (4.8%). Common treatment sites included the extremities (27%), spine (21%), abdominopelvic cavity (19%), head and neck (13%), and brain (10%). The most common presenting symptom for palliation was pain, representing 58% of palliative RT courses. Additional target symptoms included neurologic symptoms (e.g., spinal cord compression, headache, vision changes, ataxia, neurogenic bladder) in 20% of palliative RT courses and dyspnea in 10% of courses. Eleven palliative RT courses (13% of total) were performed in asymptomatic patients felt to be at high risk for symptoms from a known disease site, such as impending pathologic fracture or lesions approaching but not yet compressing the spinal cord. The median number of RT fractions delivered for each palliative course was 6 (range, 1 32) and the median number of elapsed days was 9 (range, 0 47). In eight cases (10% of courses), treatment was terminated early TABLE 1 Characteristics of patients and radiation treatment delivered in 83 palliative RT courses, January 2005 to January 2015 Median (range) or % (n) Age 10.3 years ( years) Gender Male 60% (50) Female 40% (33) Anatomic site Extremity 27% (22) Spine 20% (17) Abdomen/pelvis 19% (16) Head and neck 13% (11) Brain 10% (8) Thoracic 7.2% (6) Liver 1.2% (1) Other 2.4% (2) Histology Neuroblastoma 23% (19) Rhabdomyosarcoma 18% (15) Ewing s sarcoma 10% (8) Leukemia 7.2% (6) Osteosarcoma 4.8% (4) Other sarcoma 4.8% (4) Lymphoma 2.4% (2) Wilms tumor 2.4% (2) Brainstem glioma 1.2% (1) Ependymoma 1.2% (1) Malignant astrocytoma 1.2% (1) Other 24% (20) Indication/target symptom a Pain 58% (48) Neurologic symptoms 21% (17) Asymptomatic 13% (11) Dyspnea 10% (8) Other 10% (8) Total dose delivered 2,000 cgy (150 5,974 cgy) No. of fractions 6 fractions (1 32 fractions) Elapsed days 9 days (0 47 days) Completed prescribed course? Yes 90% (75) No 10% (8) a More than one target symptom was permitted per course. because of the declining clinical status of the patient or parental preference. Evaluation of symptom response was possible for 79 of 84 palliative RT courses. When response was not evaluable, it was generally due to the patient transferring care or enrolling in hospice shortly after completing RT, and subsequent lack of clinical notes or detailed updates from outside providers. Of the courses for which response was

3 VARMA ET AL. 3of7 TABLE 2 Success rate of palliative RT courses by indication, duration, and timing % (n) All evaluable courses 77% (61) Indication/target symptom Pain 80% (37) Neurologic symptoms 71% (10) Asymptomatic 100% (9) Dyspnea 62% (5) Other 50% (4) No. of fractions a 10 fractions 82% (46) > 10 fractions 94% (15) Timing in disease course Last 30 days of life 28% (4) >30 days of life 89% (57) b a Completed courses only. b p < evaluable, 80% of courses undertaken for pain resulted in symptom improvement, as did 71% of courses for neurologic symptoms and 62% of courses for dyspnea (Table 2). Of the 11 palliative RT courses delivered for prevention of impending symptoms, in 9 cases follow-up documentation indicated that the patient remained free of the symptom until death or last follow-up, and in the remaining 2 cases there were insufficient clinical notes to determine whether the patient developed symptoms before death (Table 2). From this point forward in our analysis, palliative RT courses were considered successful if they either led to symptom improvement in a symptomatic patient or were delivered to an asymptomatic patient and the patient remained free of the feared symptom. The overall rate of successful palliative RT courses was 77%. Characteristics of the unsuccessful courses are presented in Table 3. Unsuccessfully treated sites included the abdomen/pelvis (35% of unsuccessful courses), spine (23%), thoracic (18%), brain (12%), head and neck (6%), and extremity (6%). The most common unsuccessfully treated histologies were rhabdomyosarcoma (23%), leukemias (18%), and neuroblastoma (12%), and the most common unsuccessfully treated symptom was pain (53%). Thirty-five percent of unsuccessful courses were courses terminated early. Of the 50 individual patients treated, 43 were deceased and 7 were still living at the time of data collection. Median survival after palliative RT was 124 days, with a range from 1 day to 1141 days (Fig. 1A). Fifteen palliative RT courses were delivered to patients in the last 30 days of life (dol); seven of these were in the last 7 dol. To examine the effect of timing on the utility of palliative RT, we compared courses delivered to patients in the last 30 dol with those delivered earlier in the disease course. Palliative RT delivered in the last 30 dol had a 28% success rate, whereas courses delivered earlier than the last 30 dol had an 89% success rate (Table 1). This difference was statistically significant (p < ). Details of the patients who received palliative RT in the last 7 dol are presented in Table 4. Of note, five of the TABLE 3 Characteristics of unsuccessful completed palliative RT courses (n = 17) Median (range) or % (n) Anatomic site Abdomen/pelvis 35% (6) Spine 23% (4) Thoracic 18% (3) Brain 12% (2) Head and neck 6% (1) Extremity 6% (1) Histology Rhabdomyosarcoma 23% (4) Leukemia 18% (3) Neuroblastoma 12% (2) Wilms tumor 6% (1) Lymphoma 6% (1) Ewing s sarcoma 6% (1) Other a 23% (4) Indication/Target symptom Pain 53% (9) Neurologic symptoms 18% (3) Dyspnea 18% (3) Other b 23% (4) Total dose delivered 800 cgy (150 5,974 cgy) No. of fractions 3 (1 29) Completed prescribed course? Yes 65% (11) No 35% (6) a Other histologies included NUT midline carcinoma, mesoblastoma, signet ring colorectal carcinoma, and high-grade malignant neoplasm not otherwise specified. b Other indications included nerve root compression, hemoptysis, and abdominal distension. seven patients terminated RT early. None of the seven courses were successful. We also examined the relationship between fractionation and success of palliative RT. Completed palliative RT courses prescribed in 10 fractions had a success rate of 82% and completed courses prescribed in >10 fractions had a success rate of 94%, which was not a statistically significant difference (p = 0.43; Table 2). Sixty percent of patients were referred to our institution s pediatric palliative care team at some time in their trajectory (Table 5), and 28% of patients already had pediatric palliative care team involvement before palliative RT (Fig. 1B). Thirty-two patients were referred to hospice (64% of total cohort, 74% of deceased patients), and hospice referral was discussed with two additional families who declined referral. Eleven patients (22% of total cohort, 34% of those who received hospice care) were already enrolled in hospice when they presented for palliative RT (Fig. 1C). For those patients not already enrolled in hospice, the median time to hospice referral was 96 days after the last palliative RT fraction (range, days). The median time from

4 4of7 VARMA ET AL. TABLE 4 Characteristics and outcomes of patients receiving palliative RT in the last 7 days of life Patient Age (years) Histology Site Symptom Systemic disease status/concurrent problems Prescribed treatment (dose/# Fx) Delivered treatment (dose/# Fx) Days to death Location of death Acute myelogenous leukemia Infratemporal fossa mass Pain Progressive bony infiltration, leukemia cutis/gram-negative bacteremia 10.5Gy/3fx 7Gy/2fx 5 Hospital (floor) 2 8 Ewing s sarcoma R lung & chest wall Hemoptysis, chest pain Nootherdisease sites/anemia 25 Gy/5 fx 5 Gy/1 fx 1 ICU Neuroblastoma L hemithorax Respiratory distress No other disease sites/febrile neutropenia, hypokalemia 7.5Gy/5fx 1.5Gy/1fx 1 ICU Acute myelogenous leukemia Lumbar spine Spinal cord compression Disseminated leptomeningeal disease/hydrocephalus 20 Gy/5 fx 20 Gy/5 fx 2 ICU 5 10 Burkitt s lymphoma Abdomen/pelvis Pain Multiple abdominal masses, abdominal and bilateral iliac LNs/Fever, cardiac dysfunction 9Gy/6fx 4.5Gy/3fx 3 Hospital (floor) 6 14 Ewing s sarcoma Brain Altered mental status Progressive lung and visceral metastases/thrombocytopenia, weight loss 30 Gy/10 fx 18 Gy/6 fx 5 Unknown a 7 5 Wilms tumor Abdomen/pelvis Pain, psoas muscle dysfunction Multifocal progressive disease throughout abdomen and pelvis/urinary outlet obstruction, renal failure 8Gy/1fx 8Gy/1fx 6 Hospital (floor) a Patient was discharged from hospital with hospice care 1 day after RT.

5 VARMA ET AL. 5of7 hospice referral to death was 36.5 days (range, days). Of the 43 patients who died, the location of death was identified for 31 (72%), and of these, 55% died at home, 32% in the hospital, and 13% at an inpatient hospice facility (Table 5). 4 DISCUSSION FIGURE 1 Timing in days of palliative RT completion relative to (A) death or last follow-up, (B) first contact with the palliative care team, and (C) hospice enrollment TABLE 5 Supportive and end-of-life care patterns for 50 children treated with palliative RT Median (range) or % (n) Status a Alive 14% (7) Deceased 86% (43) Palliative care and hospice involvement Palliative care only 14% (7) Hospice only 18% (9) Both 46% (23) Neither 12% (6) Hospice length of stay 36.5 days (4 243) Location of death b Home 55% (17) Hospital 32% (10) Inpatient/residential hospice 13% (4) a Atthetimeofdataanalysis. b Of 31 patients whose location of death could be determined by the chart review. Radiation therapy is a well-established and widely used modality to palliate symptoms from advanced cancers. While palliative RT in adults is informed by large-scale clinical trials 2,3,6 and patterns of care analyses, there is little comparable literature to guide the use of palliative RT in children. Our study contributes to this literature by reporting a 10-year single-institution series of pediatric palliative RT patients, with a focus on the timing of palliative RT in the illness trajectory. Clinical outcomes in our cohort affirm that RT is effective for palliation of pain, dyspnea, neurologic, and other symptoms in children with advanced cancer. Our symptom response rates are consistent with previously reported series including the overall 84% response rate Koontz s metastatic Ewing s sarcoma series, 16 and symptom-specific response rates of 80% for bone pain, 55% for dyspnea/chest pain, and 58% for neurologic symptoms in Rahn s series of diverse histologies. 11 Interestingly, 13% of the RT courses in our cohort were to asymptomatic disease sites, where either the physician or the patient/family was concerned that symptoms could quickly develop. For example, two children were treated for large C1 C2 metastases before developing any symptoms of spinal cord compression. To our knowledge, the frequency and outcomes of such prophylactic palliative treatment have not previously been described. In our cohort, no child treated for symptom prevention was documented to develop the symptom, though of course it remains speculative how they would have fared without RT. The success rate of palliative RT in our cohort was significantly lower for children in their last 30 dol. This is unsurprising given the usual dynamics of RT response 17,18 and is consistent with growing consideration of RT in the last 30 dol as a potential overuse metric for adult patients. 19,20 Whether the designation of overuse is appropriate for palliative RT in children in the last 30 dol is unclear, as prognostication to this level of specificity can be extremely challenging and some children in their last 30 dol did appear to benefit. Experienced clinician judgment, potentially augmented by published survival prediction models, can often produce reasonable life expectancy estimates at least in general terms of hours, days, weeks, or months. Life expectancy on the order of days to weeks should probably attenuate clinician and family expectations of benefit from RT, though attempting treatment may still be reasonable for intractable symptoms. Most children in our cohort treated in the last 7 dol were unable to complete the prescribed course, and none appeared to have symptom improvement from the dose they did receive. Many of these children had widely disseminated progressive disease or other serious medical problems at the time palliative RT was attempted, likely driving their short survival. If palliative RT is attempted for an intractable focal symptom when life expectancy is on the order of days, strong consideration should be given to

6 6of7 VARMA ET AL. single-fraction treatment to increase the likelihood that the patient will actually receive a therapeutic dose. Even for children earlier in their disease trajectory, shorter palliative RT courses have the important advantage of imposing fewer burdens on the child and family. Our results did not indicate a greater likelihood of success with protracted RT courses, >10 fractions. However, with conventional fractionation sizes, longer courses may offer more durable response and less long-term toxicity. With median survival on the order of 3 4 months, late effects should be of less concern in this population, though we did see a few multiyear survivors. There is growing interest in stereotactic radiation in the pediatric population, exemplified by the current Children s Oncology Group phase II clinical trial for metastatic Ewing s sarcoma in which a secondary outcome is the feasibility of stereotactic body radiation therapy. Hypofractionated stereotactic radiation might prove useful in the palliative setting as well, for children in whom durability of response and/or late effects are of concern. Our data are reassuring that children receiving palliative RT were able to access other important supportive care and end-of-life services. Altogether, 88% of children treated with palliative RT were also referred to either our institution s pediatric palliative care team or hospice, including 22% of the cohort who were already enrolled in hospice when they received RT. This is in contrast to the adult population, where access to palliative RT while enrolled in hospice can be quite limited. 15,21,22 For those children referred to hospice after palliative RT, this tended to happen weeks to months later, further suggesting that palliative RT and hospice were utilized with distinctive roles and timing in the continuum of care. This is again in contrast to our experience (S.V. and M.J.S.) with adult palliative RT patients, for whom hospice and palliative RT are often treated as competing options of last resort when nothing more can be done with systemic therapy. The median time from hospice referral to death in this pediatric cohort was 36.5 days, which is 5 6 days shorter than that reported in other studies of pediatric oncology patients in hospice. 23,24 This does raise the prospect that palliative RT might delay some hospice referrals, but may also reflect broader institutional or regional differences. These considerations highlight the importance of close multidisciplinary collaboration in the care of children for whom palliative RT is considered. Selecting patients who are likely to benefit from RT and matching the appropriate RT strategy to the patient depends on a clear understanding of the child s disease trajectory, global medical condition, prognosis and prognostic awareness, and other symptom management options if RT is infeasible or unsuccessful. The primary pediatric oncologist has a key role to play, utilizing their expertise about the primary disease and usually a long-standing relationship with the child and family to rationally time the introduction of other specialists and services. Direct communication and cross-disciplinary education among pediatric oncologists, radiation oncologists, pediatric palliative care physicians, and other pediatric specialists, such as pain management or critical care, can help determine the best interventions for each child at different points in their course of illness. Our ability to optimize dose and fractionation for palliative RT in children would also benefit tremendously from pooling of data across centers. Multi-institutional retrospective analyses would be beneficial, as would the prospective study of symptom response to RT for various pediatric cancer histologies and symptoms. Some of these data could even be collected in the context of clinical trials for definitive therapies, as a secondary outcome to the primary survival and progression endpoints. Given the collaborative relationships within pediatric oncology clinical trials groups, it should be possible to develop evidence-based recommendations for palliative RT in children whose goals have shifted from cure to symptom control. Our study has several important limitations. It represents a singleinstitution experience, and the small number of patients precludes extensive hypothesis testing or multivariate analysis. In addition, although the charting of RT treatment details is relatively standardized, extraction of other key data points from patient charts required more subjective inference. This was particularly the case for assessing symptom onset and response, given the diversity of symptoms, absence of standardized scales from our routine clinical charting, and in some cases multiple simultaneous interventions directed at the same symptom (e.g., titration of opioids just before RT). ACKNOWLEDGEMENTS Study data were managed using REDCap electronic data capture tools hosted at Vanderbilt University, which are supported by grant UL1 TR from NCATS/NIH. CONFLICT OF INTEREST The authors declare that there is no conflict of interest. REFERENCES 1. Kim EY, Chapman TR, Ryu S, et al. ACR Appropriateness Criteria( R ) non-spine bone metastases. J Palliat Med. 2015;18(1): Lutz S, Berk L, Chang E, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. 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