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Palliative radiotherapy at the end of life: A critical review

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Introduction
In 2013, the Institute of Medicine released Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis, detailing the many complex issues patients and providers face in the changing health care environment. 1 Key among the recommendations of the committee were engaging patients and providers in ongoing and open discussions regarding prognosis; the benefits and harms of treatments; navigating changing cost and payment structures; and supporting patient preferences through the continuum of care, including end-of-life care. In the setting of advanced cancer, the committee noted the significant variability in aggressiveness of end-of-life care around the United States, 2,3 and the Institute of Medicine committee recommended providing patients with information and care consistent with their needs, values, and preferences, including timely referral to hospice. However, care near the end of life varies widely by hospital and geographic area. 2 In addition, patient misconceptions of the goals of therapy persist, with up to 70% of patients with metastatic colorectal cancer and up to 80% of patients with metastatic non-small cell lung cancer not understanding that chemotherapy was "not at all likely" to cure their cancer. 4 Similar misconceptions persist in other areas of cancer treatment, with up to 64% of patients receiving palliative radiotherapy for metastatic non-small cell lung cancer misconstruing the intent of therapy. 5 Based on studies of early palliative care for patients with metastatic cancer, improvement in patient understanding of the intent of therapy appears to have an impact on the aggressiveness of cancer care toward the end of life, including receipt of chemotherapy in the last 60 days of life and rates of hospice use. 6 It is in this context that the current review of palliative radiotherapy near the end of life is presented.
For more than a century, palliative radiotherapy has been a cost-effective, time-efficient treatment to help patients manage the symptoms of advanced and metastatic cancer. 7 In the most general terms, palliative radiotherapy may be effective in controlling pain, neurologic symptoms, and obstructive symptoms and providing local control of tumors in any organ system in the body. Palliative radiotherapy may be considered in any patient in whom local tumor is causing symptoms ( Table 1). 1 Assistant Professor, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA; 2 Medical Director, Department of Radiation Oncology, Blanchard Valley Regional Cancer Center, Findlay, OH; 3 Professor, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; 4 Professor, Department of Radiation Oncology, University of Indiana, Indianapolis, IN However, time to optimal symptom control, even after short courses of radiotherapy, is usually measured in weeks to months after radiation treatments are delivered, as clearly demonstrated in the case of pain relief from bone metastases. 8,9 In spite of this delay in efficacy, recent reports have found that many patients receive courses of radiotherapy in the final weeks or months of life. [10][11][12][13] When survival is short, palliative radiotherapy may have minimal, if any, clinical benefit for patients, may delay referral to hospice, and may impede optimal end-of-life planning and care delivery ( Table 2). In 2010, Lutz et al explored the concept of when palliative radiotherapy has value and when it does not. 14 This review updates their findings, with a focus on the recent literature, the use of prognostic models to guide decision-making in palliative radiotherapy referrals, and treatment decisions in specific instances in which palliative radiotherapy may be beneficial.

Patterns of Palliative Radiotherapy Use at End of Life
The National Quality Forum (NQF) lists chemotherapy use within the last 14 days of life, intensive care unit (ICU) admissions during the last 30 days of life, more than one emergency room visit within the final days of life, and hospice admission for fewer than 3 days or not at all as indicators of lower-quality care, conclusions that are endorsed by the American Society of Clinical Oncology. 15 The NQF has also recently endorsed palliative radiotherapy dose fractionation schemes that follow the American Society for Radiation Oncology (ASTRO) evidence-based guidelines (30 gray [Gy] in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction) as a quality indicator in palliative radiation oncology. 16 However, although palliative radiotherapy use within the last 14 or 30 days of life may impact these other quality measures, it has not, on its own, been defined as a specific quality measure. As such, an "optimal" rate of palliative radiotherapy use near the end of life (either within 14 or 30 days of death) is unknown. Rates that are very low might indicate underuse of palliative radiotherapy, meaning that some patients who might have benefitted from radiation are not being treated, whereas rates that are very high might indicate overuse and an excessive burden of radiotherapy without significant clinical benefit. Nonetheless, several recent studies have begun to explore radiotherapy use at the end of life.
Multiple population-based and descriptive studies have explored rates of palliative radiotherapy use at end of life in various contexts (Table 3). 10,12,13,[16][17][18][19][20][21][22] These studies provide a starting baseline of characteristics of patients receiving radiotherapy near the end of life. Although the number of patients receiving radiotherapy in the final 14 days, 30 days, or 45 days of life varies based on multiple factors, many of these patients will not live long enough to achieve clinical benefit from palliative radiotherapy. Moreover, as each type of study indicates, many patients with short survival after radiotherapy receive extended dose fractionation schemes within the final 30 days of life, potentially increasing side effects compared with shorter dose fractionation schemes and possibly delaying hospice referral or other end-of-life care and planning. Accurate prognostication would allow patients who might live long enough to benefit from radiotherapy to have   Retrospective single-institution review 52 l Review of palliative radiotherapy patients who died shortly after completion of treatment l 78% did not complete their intended course l Median time from treatment completion to death was 4 d l None of the patients were prescribed single-fraction therapy model does not exist (and is likely not to exist) because models for patients with a likely longer life expectancy often account for tumor histology and stage whereas histology and stage do not necessarily impact prognostication in patients with a shorter life expectancy. 23 Communicating prognosis is a complicated task that requires an assessment of patient expectations and information desired and an explanation of the statistical data used (median survival), as well as typical, best-case, and worst-case scenarios. 27,28 It is beyond the scope of this review to detail the extensive work done on prognostication in patients in advanced cancer, although several studies relevant to the survival prognostication of patients receiving radiotherapy have been completed and provide a good backdrop for evaluation of the topic. The simplest prognostic model for survival in patients with advanced cancer would be clinician prediction of survival. However, multiple prospective studies and systematic reviews have confirmed that clinicians are frequently inaccurate in survival estimates and tend to be overly optimistic of survival time, even in patients with short expected survival. [29][30][31][32] These findings of clinician inaccuracy in the prediction of survival have been corroborated among patients referred to palliative radiotherapy programs (Table 4). 20,33,34 Various prognostic models have been developed to help predict survival among patients with advanced cancer and a short life expectancy. Krishnan et al recently reviewed general prognostic models for predicting life expectancy in patients with advanced or incurable solid malignancies not limited to a single cancer type or clinical scenario. 23 Among 13 prognostic models reviewed, the authors found that the most common characteristics predictive of survival in the various models included PS; clinical symptoms including anorexia/cachexia syndrome (loss of appetite with or without weight loss), dyspnea, nausea, dysphagia, and confusion; and laboratory values including lactate dehydrogenase, C-reactive protein, albumin, leukocytosis, and lymphopenia, with fewer studies including primary tumor site, metastasis characteristics, or physician survival prediction in the prognostic model. The majority of these models for short survival were developed among patients in medical oncology or palliative care clinics, palliative care inpatient units, or hospice programs. As such, their validity among patients referred for palliative radiotherapy is unknown.

Prognostic Models for Patients With Advanced Cancer Referred for Palliative Radiotherapy
Two prognostic models for survival among patients referred for palliative radiotherapy have been developed in addition to numerous cancer-specific or metastasis-specific models of prognostication (Table 5). 23,33,35 The "number of risk factors" model developed and validated by Chow et al 35,36 was first developed by analyzing 16 factors potentially predictive of survival among 395 patients referred for palliative radiotherapy in 1999. Six factors were found to have an impact on survival on Cox modeling: primary cancer site, metastasis site, Karnofsky performance status (KPS), fatigue, appetite, and dyspnea (all measured with the Edmonton Symptom Assessment Scale [ESAS]). The validation data used 2 methodologies to validate the initial model among 445 patients included in the prospective database. The authors validated the data using both a "partial score" method in which they assigned a weight to each factor based on the training set data to construct a survival prediction score and a "number of risk factors" method in which the adverse risk factors from the initial data set were nonbreast cancer primary site, metastases to other Retrospective single-institutional review 793 l Six radiation oncologists estimated survival for patients referred for palliative radiotherapy consultation l Median overall survival for all patients was 15.9 wk l The average survival overestimation was 12.3 wk l Survival overestimation was 21.9 wk for those who lived less than 3 mo Fairchild 2014 34 Prospective single-institutional review 155 l Physicians, nurses, radiation therapy technologists, and allied health professionals estimated survival for patients referred for palliative radiotherapy consultation l Median survival for all patients was 87 d l 72% of estimates were overly optimistic l Physician estimates were slightly less accurate than those made by nurses and radiation therapy technologists CA CANCER J CLIN 2014;64:296-310 VOLUME 64 _ NUMBER 5 _ SEPTEMBER/OCTOBER 2014 than bone only, KPS of 50 or less, fatigue score of 4 to 10 on ESAS, appetite score of 8 to 10 on ESAS, and a shortness of breath score of 1 to 10 on ESAS. For each validation method, the probability of survival at 3, 6, and 12 months was estimated. It was found that 0 to 3, 4, or 5 to 6 risk factors discriminated survival equally to the partial score method with 3-month, 6-month, and 12-month survival probabilities of 80%, 64%, and 41%, respectively, for patients with 0 to 3 risk factors; 51%, 25%, and 10%, respectively, for patients with 4 risk factors; and 29%, 13%, and 3%, respectively, for patients with 5 or 6 risk factors. This model provides a general framework for evaluating likely survival among patients referred for palliative radiotherapy in an outpatient clinic. The authors caution that the model has been validated at the population level and again stress the need for individualized counseling regarding the meaning of the model for individual patients. Krishnan et al recently proposed a second model for the prediction of survival among patients referred for palliative radiotherapy: the TEACHH (Type of cancer, ECOG PS, Age, prior Chemotherapy, prior Hospitalizations, Hepatic metastases) model. 37 In this model, 862 records of patients treated with palliative radiotherapy between 2008 and 2011 were reviewed retrospectively to generate a model capable of predicting short (less than 3 months) and long (greater than 1 year) life expectancy. The median survival for all patients was found to be 5.6 months. Factors found to be significant predictors of survival included type of cancer (lung and other vs breast and prostate), PS (Eastern Cooperative Oncology Group PS of 2-4 vs 0-1), age (>60 years vs 60 years), prior palliative chemotherapy (2 courses vs 0 or 1 course), prior hospitalizations within 3 months of radiotherapy (0 vs 1 or more), and liver metastases (present vs absent). Using a number of risk factors model, the authors were able to define 3 distinct groups with different median survivals: patients with 0 or 1 risk factor had a median survival of 19.9 months, patients with 2 to 4 risk factors had a median survival of 5.0 months, and patients with 5 or more risk factors had a median survival of 1.7 months. Although this model has not yet been validated externally, it holds promise for extending the work of Chow et al 35,36 in helping to discriminate those patients referred for palliative radiotherapy into groups with a short life expectancy (who may be less likely to benefit from palliative radiotherapy) and those with a likely longer life expectancy. Other models for survival estimation for specific clinical scenarios (such as brain metastases or metastatic spinal cord compression) will be explored in more detail under each clinical scenario below.

Specific Clinical Scenarios for Radiotherapy Use at End of Life Radiotherapy Management of Bone Metastases
Multiple randomized controlled trials and several systematic reviews over the past 30 years have demonstrated the efficacy of radiotherapy in palliating pain from uncomplicated bone metastases. 9,[38][39][40] Overall, approximately 25% of patients can expect to have complete pain relief whereas a total of 60% of patients can expect some response to radiotherapy. According to the ASTRO guidelines for the management of bone metastases, a single fraction of 8 Gy is  23 has not yet been validated.
equivalent to longer courses of radiotherapy, including 5 or 6 fractions of 4 Gy and 10 fractions of 3 Gy. 41 These dose fractionation schemes are recommended as quality indicators of palliative radiotherapy by the NQF. 16 Acute and late side effects of radiotherapy for bone metastases are generally similar with single-fraction versus multifraction regimens, with some studies showing decreased acute side effects in patients receiving single-fraction radiotherapy. Time to pain relief also appears similar, with an optimal time to measure pain relief of 2 months after the completion of palliative radiotherapy. 8 In patients with survival of greater than one year, single-fraction treatment provides noninferior pain relief and freedom from pathologic fracture and long-term side effects when compared with fractionated courses, although retreatment rates may be up to 2.6 times more likely with single-fraction therapy. 40,42 Furthermore, successful single-fraction treatment may well provide secondary relief in the form of diminished cost and side effects caused by narcotic pain analgesics. Caregivers and loved ones surely appreciate the option to choose an efficient and effective means by which to alleviate disease symptoms and the toxicity of pain medicine by means of one shared decision. Moreover, there is now randomized evidence demonstrating the efficacy of repeat irradiation in patients initially treated with a single fraction of 8 Gy or 5 fractions of 4 Gy, with up to 50% of patients having symptom improvement after reirradiation. 43 Despite these data regarding the equivalence of longcourse and short-course radiotherapy, multifraction regimens are still commonly used in the United States and around the world with the adoption of single-fraction radiotherapy based primarily on training and geographic location. [44][45][46] A recent population-based study by Bekelman et al examining palliative radiotherapy for patients with prostate cancer with bone metastases in the Surveillance, Epidemiology, and End Results-Medicare database showed that an only 3.3% of 3050 patients received single-fraction radiotherapy for bone metastases, whereas 50.3% received 11 or more fractions. 47 Although differences in survival are not expected among patients who receive different dose fractionation regimens for bone metastases, this analysis revealed a median survival of 5.0 months for patients receiving single-fraction radiation and 11.9 months for patients receiving more than single-fraction radiation, suggesting that radiation oncologists tend to use multifraction radiotherapy for patients with longer anticipated survival. Nevertheless, given its equal efficacy and greater convenience even for patients with longer survival, many individuals and groups advocate for the use of single-fraction radiotherapy for patients with uncomplicated bone metastases regardless of prognosis. 48,49 The influence of reimbursement based on the length and complexity of treatment course on physician behavior is not fully understood, yet this model persists in the United States and may be one of the causes for the reluctance to offer single-fraction treatment for appropriate patients. Although exact estimates of cost depend upon several variables, a single fraction may cost less than one-half that of a fractionated course, and potentially several times less than stereotactically delivered treatments.
Studies have confirmed the efficacy of palliative radiotherapy for painful bone metastases, even among patients with limited life expectancy (Table 6). 26 Therefore, survival prediction should impact radiotherapy for bone metastases only if anticipated survival is less than 4 weeks because patients with such short anticipated survival are unlikely to benefit from radiotherapy (Table 7). Using the proposal from Gripp et al, the percentage of remaining life spent receiving palliative radiotherapy may be a useful metric to evaluate the utility of radiotherapy in patients with short anticipated survival. 21 If some patients are able to receive benefit, even with very short survival, it may be reasonable to offer single-fraction radiotherapy with the goal of minimizing inconvenience and side effects while still potentially providing benefit from palliative radiotherapy. This is an open and unexplored question. In the interim, the Dutch Bone Metastasis Study criteria of a KPS less than 40 alone may be a sufficient predictor of survival to guide radiotherapy decision-making in patients with advanced cancer. 42 Validation of the TEACHH model may also help to clarify the usefulness of palliative radiotherapy for bone metastases at the end of life. 37  55 Rades et al conducted a matched pair analysis and found similar rates of ambulatory status, local control, and survival among patients treated with surgery plus radiotherapy versus those treated with radiotherapy alone. 56 Multiple studies have focused on prognostic factors and appropriate radiotherapy dose fractionation for patients diagnosed with MESCC (Tables 8 and 9). [57][58][59][60][61][62][63] An overview of these studies reveals that radiotherapy plays an important role in the management of MESCC, allowing for improvements in pain control, motor function, and durable responses, thus limiting the likelihood of recurrent MESCC. Radiotherapy is estimated to restore ambulation in approximately 60% of patients with MESCC, although that estimate is variable and depends on several factors such as tumor histology, absence of mechanical compression by fractured bone, and interval since the onset of symptoms. Surgery also plays an important role in patients with good prognosis, one area of cord compression, and spinal instability. However, although the role of radiotherapy versus best supportive care in patients with poor prognosis and MESCC is still being explored, the available data can provide a suggested decision tree for treatment options by clinical circumstance (Table 10). If validated, use of the prognostic score developed by Rades et al for patients with anticipated short survival would provide a valuable tool to assist with decision-making regarding radiotherapy use near the end of life in patients with MESCC. 63 The concept of the percentage of remaining life spent receiving palliative radiotherapy may be the basis of a quality indicator, potentially allowing patients to benefit from palliative radiation for MESCC without significant burden. Potential adjuvant treatments include: l Pain medication including nonsteroidal antiinflammatory medicines, steroids, narcotic analgesics, antidepressants, antiseizure medicine for neuropathic pain l Radiopharmaceuticals for widespread painful and osteoblastic bone metastases l Bisphosphonates to promote osteoblast activity and to diminish the risk of formation of additional bone metastases l Nerve root injection Gy indicates gray.

Whole-Brain Radiotherapy in Patients With Brain Metastases
Similar to the management of malignant epidural spinal cord compression, the management of brain metastases involves a multidisciplinary approach including radiation oncologists, neurosurgeons, medical oncologists, and palliative care providers. The ASTRO guidelines for the management of brain metastases describe several algorithms, including the use of neurosurgical resection, stereotactic radiosurgery (SRS), whole-brain radiotherapy, and best supportive care based on the number and size of brain metastases, resectability, and anticipated prognosis based on a number of prognostic models. 64 Resection seems most reasonable for patients with good PS and favorable prognosis whose disease is confined to a single lesion measuring less than 3 to 4 cm in diameter and that is anatomically located in a site that can safely be approached surgically. Patients with adequate PS and a single lesion measuring  less than 3 to 4 cm in size that is not amenable to safe complete resection should be considered for SRS. For those with multiple brain metastases, SRS can also be considered for patients with a favorable prognosis and a limited number of appropriately sized lesions. Whole-brain radiotherapy may be offered to patients after surgical resection or SRS in an attempt to address occult metastases, although the risk of cognitive difficulties increases with this approach. Whole-brain external beam radiotherapy alone remains the standard of care for patients who do not have disease that qualifies for treatment with resection or SRS, although patients with extremely poor prognoses may be best treated with supportive care alone. Of note, multiple studies have confirmed the equivalence of various dose fractionation schemes for whole-brain radiotherapy, including 5 fractions of 4 Gy, 10 fractions of 3 Gy, 15 fractions of 2.5 Gy, and 20 fractions of 2 Gy without statistically significant differences in overall survival or symptom control noted among the regimens. 64,65 Improvement in neurologic symptoms should be expected in approximately two-thirds of patients who undergo palliative external beam radiotherapy. Various studies have evaluated the available prognostic instruments while seeking the optimal treatment of this patient group (Table 11). [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] Thus, the management of brain metastases has evolved significantly over the past 30 years, but challenges remain in the treatment of patients with brain metastases and poor prognosis. Although whole-brain radiotherapy may offer some clinical benefit, the extent of this benefit remains poorly defined, particularly in patients with short survival. Continued work on prognostic models that predict short survival (1 month or less) will allow better decisionmaking and care for patients with brain metastases near the end of life (Table 12). Alternative approaches to determining the role of radiotherapy in patients with brain metastases have also been examined through program development. An integrated, team-based palliative oncology clinic including radiation oncologists, palliative care clinicians, and nursing and allied Potential adjuvant treatments include: l Chemotherapy or targeted immunotherapy for symptomatic locoregional disease for which further surgery or radiotherapy cannot be safely delivered or for symptomatic visceral metastases l Hormonal therapy for breast or prostate cancer, if not previously delivered l Radiopharmaceuticals for multifocal, symptomatic bone metastases l Medication or nerve root injection for intractable pain

Rodrigues 2013 66
Comparison of existing prognostic instruments l Nine existing prognostic instruments were compared l Factors used to predict outcome were similar but not identical across these tools l Major misclassification rates varied from 2% to 39%, with 6 of the 9 instruments having misclassification rates >25% l The 2 instruments with the lowest misclassification rates have not yet been validated Nieder 2013 77 Retrospective analysis l A total of 124 patients with poor prognosis who received best supportive care, whole-brain radiotherapy, or stereotactic radiosurgery l Factors favoring best supportive care rather than radiotherapy included age 75 y, KPS 50, and uncontrolled primary tumor with extracranial metastases to at least 2 organs Craighead 2012 78 Population-based study, Alberta, Canada l A total of 568 poor-prognosis patients treated with whole-brain radiotherapy l Overall survival was 3 mo, with factors predicting poor prognosis including low KPS, advanced age, and a larger number of brain lesions Langley 2013 79 Ongoing prospective randomized trial l Randomization of poor-prognosis patients with non-small cell lung cancer metastasized to brain between best supportive care plus whole-brain radiotherapy vs best supportive care alone l Interim report suggests no improvement in overall survival or quality of life for patients treated with wholebrain radiotherapy Nieder 2013 80 Retrospective analysis l Patients with brain metastases, poor prognosis, and diagnoses other than non-small cell lung cancer l The addition of whole-brain radiotherapy did not add to median survival other than perhaps a slight amount in those with small cell lung cancer metastases KPS indicates Karnofsky performance score.
health professionals saw 100 consecutive patients with brain metastases between January 2011 and May 2012. A total of 75 patients ultimately received radiotherapy, whereas 25 were treated without radiotherapy, either due to patient preference or rapid clinical deterioration. 81 The authors found that with the joint clinic with palliative care and radiation oncology, the number of patients who received wholebrain radiotherapy within 30 and 14 days of death decreased from 19% to 9% and 6% to 1%, respectively, based on historical rates at the same institution. Such multidisciplinary assessments could help patients, families, and clinicians with complex decision-making regarding whole-brain radiotherapy versus supportive care near the end of life.

Palliative Thoracic Radiotherapy
Palliative thoracic radiotherapy for patients with very locally advanced or metastatic lung cancer or lung metastases can be highly effective in the palliation of symptoms related to advanced cancer in the lung, including cough, hemoptysis, dyspnea from airway obstruction, symptoms of superior vena cava syndrome, and chest pain. After radiotherapy, intrathoracic symptom relief is excellent and includes palliative rates of 40% to 97% for dyspnea, 77% to 92% for hemoptysis, 60% to 91% for cough, and 70% to 78% for pain. In contrast to the data for bone and brain metastases, there appears to be a survival advantage for patients with a good prognosis who are treated with higher doses of radiotherapy. Two influential studies have examined the use palliative radiotherapy in this setting (Table 13). 82,83 These data have been summarized in the ASTRO evidence-based guidelines for palliative radiotherapy for lung cancer. 84 The guidelines suggest shorter courses of radiotherapy for patients with poor PS and describe no role for upfront concurrent chemoradiotherapy or endobronchial brachytherapy for the palliation of advanced/metastatic lung cancer. At the current time, the primary factors that influence radiotherapy dose fractionation schemes for thoracic radiotherapy should continue to be PS and comorbidities while prognostic models continue to be evaluated (Table 14).

Other Symptoms Palliated by Radiotherapy
There are myriad other symptoms that may be palliated by radiotherapy, including dysphagia from esophageal cancer; bleeding, pain, and obstruction from head and neck cancer; pelvic pain and bleeding from advanced gynecologic, gastrointestinal, and genitourinary malignancies; and neurologic Whole-brain radiotherapy alone Whole-brain radiotherapy plus radiosurgery Radiosurgery alone l If any lesion > 4 cm in size: Whole-brain radiotherapy alone Prognosis > 1 mo (solitary metastasis) l If completely resectable, then surgery plus whole-brain radiotherapy, radiosurgery, or both l If not completely resectable but <4 cm, then radiosurgery alone or with whole-brain radiotherapy l If not completely resectable and >4 cm, then whole-brain radiotherapy alone  Meta-analysis of prospective randomized trials l Evaluated 13 radiotherapy regimens used in randomized trials l There was no significant difference in symptom control with short courses of radiotherapy (ranging from a single fraction of 8 Gy to 10 Gy, 17 Gy in 2 fractions one wk apart up to 35 Gy in 10 fractions over 2 wk) to longer courses of radiotherapy with higher doses (ranging from 17 Gy in 2 fractions one wk apart to 60 Gy in 30 fractions over 6 wk) l There appeared to be a survival advantage for patients with good prognosis treated with higher doses of radiotherapy l A biological equivalent dose of 35 Gy in 10 fractions had a higher survival rate with 26.5% vs 21.7% of patients treated with high-dose vs low-dose radiotherapy alive at one y and 8.1% vs 6.7% alive at 2 y l Rates of pneumonitis and myelopathy were very low, but slightly higher in the high-dose arms Chen 2013 83 Prospective observational study l Evaluated patterns of radiotherapy care for patients with non-small cell lung cancer at multiple institutional sites l Of those patients treated to the chest, 65% received >30 Gy whereas 33% received >50 Gy l Patients treated in integrated networks (the Veterans Affairs Administration of Health Maintenance Organizations) received fewer fractions whereas those who received chemotherapy received more fractions Gy indicates gray.
CA CANCER J CLIN 2014;64:296-310 VOLUME 64 _ NUMBER 5 _ SEPTEMBER/OCTOBER 2014 symptoms including pathologic brachial plexopathy or blindness from orbital metastases. 14 The theoretical benefits and burdens associated with these clinical scenarios have remained unchanged since the first description by Lutz et al in 2010, 14 but comparatively little work has been done to evaluate prognostic models and optimal palliative outcomes for these patients compared with those referred for the palliation of bone metastases, MESCC, and brain metastases. In this context, the palliation of lung cancer can be used as a model for considering the role of short-course versus longcourse versus best supportive care in patients referred for palliative radiotherapy. There are ongoing opportunities to further define optimal palliative radiotherapy regimens in each of these clinical scenarios along with prognostic indices that may help to guide the optimal use of palliative radiotherapy. Algorithms for the use of palliative radiotherapy in specific clinical scenarios have recently been outlined, including estimation of likely survival and weighing the risks of the side effects of longer versus shorter dose fractionation schemes versus improved local control and palliative benefit from the same longer dose fractionation schemes and the use of advanced technologies including intensity-modulated radiation therapy and image-guided radiation therapy. 85 General principles also hold for times when palliative radiotherapy may not be worthwhile. Palliative radiotherapy is not likely to be worthwhile when death is imminent, when radiotherapy would palliate a single symptom among many, when neither the patient nor proxy are able to consent, when radiotherapy would exceed normal tissue tolerance to radiotherapy, when treatment would be excessively lengthy or expensive, or when radiotherapy facilities are not available in a given clinical scenario. Models continue to grow, encouraging increased collaboration between palliative care clinicians and radiation oncologists, and therefore it is hoped that a lack of coordination of care between radiotherapy and palliative care/hospice physicians will become a smaller issue moving forward.

Palliative Radiotherapy Use and Hospice
Hospice is a philosophy of care and a medical benefit in the United States that involves a team approach to care for patients with life-limiting illness. The focus of care is on providing care that fits with patient needs, including symptom management and emotional and spiritual care for the patient and family. 86 There is no inherent conflict between palliative radiotherapy and hospice care because radiotherapy can be highly effective in palliating the symptoms of advanced cancer. Nevertheless, palliative radiotherapy is infrequently used in patients enrolled in hospice. Lutz et al used a survey to explore potential barriers to palliative radiotherapy use in hospice care with a survey of hospice providers' understanding and use of palliative radiotherapy. 87 The authors found that most hospice professionals believe radiotherapy is an effective treatment for symptom management in patients with advanced/metastatic cancer. However, less than 3% of the 480 hospice programs surveyed actually offered palliative radiotherapy. Impediments to closer collaboration between hospice clinicians and radiation oncologists include cost, transportation difficulties, short life expectancy, and a lack of collaboration/education among palliative care clinicians and radiation oncologists, including a lack of willingness on the part of radiation oncologists to offer single-fraction radiotherapy. The previously described population-based study of Medicare patients receiving hospice care who received palliative radiotherapy within 30 days before death demonstrated long radiotherapy courses before hospice, potentially delaying hospice referral and end-of-life planning with a very small number of patients excluded from that analysis because they received radiotherapy while on hospice. 18 Schuster et al conducted an updated survey of hospice professionals with a smaller sample size (16 licensed hospices) and found differences in knowledge regarding the equivalence of single-fraction and multifraction palliative radiotherapy among hospice physicians, hospice nurses, and hospice administrators. 88 Among this group, less than 1% of patients were referred to a radiation oncologist, based on concerns about cost and transportation burden. A study by Jarosek et al examined Medicare's Healthcare Cost Report Information System to determine rates of palliative radiotherapy use among Medicare-certified freestanding hospices during the year 2002 to explore barriers to radiotherapy use in hospice. 89 Overall, 23.8% of freestanding hospice programs offered radiotherapy, with hospice size (larger), profit status (nonprofit), and length of Medicare certification being associated with the availability of radiotherapy services. The authors concluded that reimbursement practices are at least in part responsible for the low rates of palliative radiotherapy use among hospice patients. Given the potential for collaboration between hospice and radiation oncology professionals, Schuster et al have created a dedicated hospice palliative radiotherapy program to allow for affordable and efficient radiotherapy for patients on hospice. 90 Such innovative models will be necessary to continue to bridge the worlds of hospice and palliative radiotherapy to allow for the optimal care of patients, even those on hospice, who might benefit from radiotherapy.

Palliative Radiotherapy Use in the ICU
Radiotherapy can potentially be beneficial for patients in the ICU, but outcomes of radiotherapy for patients receiving maximal support in the ICU have not been well described in the literature. By definition, a patient requiring ICU-level care has a poor PS and potentially poor prognosis, but does that mean that patients in the ICU never benefit from radiotherapy (palliative or definitive)? Most likely not. A recent retrospective analysis of intubated patients in the ICU with malignant airway obstruction who were treated with palliative radiotherapy found that 26 patients over 10 years were treated with radiotherapy. Seven patients were able to be extubated (27%), with 6 of those 7 patients ultimately discharged to home. Nevertheless, the median overall survival was 0.36 months with a range up to 113 months, demonstrating the wide range of survival in patients treated with radiotherapy in the ICU. However, to our knowledge, this study is unique in its examination of intubated patients requiring ICU-level care. In patients who would almost certainly die without radiotherapeutic intervention, does the calculus need to be different in analyzing radiotherapy near the end of life? Is a higher percentage of patients receiving radiotherapy near the end of life acceptable if the potential benefit of radiotherapy could include long-term survival? Many questions remain to be answered about the role and initiation of radiotherapy in intubated patients in the ICU.

Conclusions
Palliative radiotherapy can be highly beneficial to patients with advanced or metastatic cancer causing significant symptoms. Radiotherapy can be used to help with pain relief in the management of bone metastases, neurologic symptoms in patients with MESCC, and brain metastases and other symptoms that cause focal symptoms from local tumor progression. However, the role of radiotherapy in patients toward the end of life continues to be clarified. Prognostic models can help to predict survival, but challenges continue to exist in understanding the clinical benefits versus burdens for patients with anticipated short survival. Patients with bone metastases can potentially have pain relief, sometimes within a few weeks of the completion of radiotherapy. Similarly, patients with MESCC may have significant clinical benefit from radiotherapy, but the benefit remains unclear in patients toward the end of life. The optimal management of patients with brain metastases and poor prognosis is being actively studied among patients with metastatic non-small cell lung cancer in the QUARTZ trial in the United Kingdom. Further studies should continue to explore the question of when radiotherapy is worthwhile and when it is futile.
Larger questions persist regarding whether radiotherapy administered in the last 14 days, 30 days, or even 60 days of life might be useful as a quality indicator. Other measures of aggressiveness of care at end of life including chemotherapy, visits to the emergency department, hospitalizations, and ICU stays have been described as quality measures by the American Society of Clinical Oncology and the NQF, but palliative radiotherapy at end of life has not. If radiotherapy at end of life is considered as a quality indicator, what should the measurement be? Receipt of radiotherapy in the final 14 or 30 days of life could potentially measure aggressiveness of care, but does not account for differences in risk/benefit calculi between single-fraction radiotherapy and multifraction radiotherapy regimens. As such, if radiotherapy at the end of life is to be incorporated as a quality indicator, we would recommend using the percentage of remaining life spent receiving radiotherapy as the indicator with a cutoff of 10% of remaining days receiving radiotherapy as a potential indicator that merits further exploration. Regardless of whether radiotherapy at the end of life is determined to be a quality indicator in evaluating palliative radiotherapy, a number of other questions remain to be explored: 1. What prognostic models are most likely to be clinically useful to help classify which patients are likely to have prolonged survival and which patients are likely to have short survival? 2. How can these prognostic models be incorporated into practice to allow clinicians to use evidence-based medicine in recommending palliative radiotherapy treatments? 3. If palliative radiotherapy is being underused, how can increased collaboration among radiation oncologists, medical oncologists, surgical oncologists (including neurosurgeons), and palliative care clinicians improve referral rates for radiotherapy that may help with symptom control? 4. What are the optimal dose fractionation schemes for patients with visceral metastases and a short life expectancy?