Palliative radiotherapy at the end of life: a critical review.

When delivered with palliative intent, radiotherapy can help to alleviate a multitude of symptoms related to advanced cancer. In general, time to symptom relief is measured in weeks to months after the completion of radiotherapy. Over the past several years, an increasing number of studies have explored rates of radiotherapy use in the final months of life and have found variable rates of radiotherapy use. The optimal rate is unclear, but would incorporate anticipated efficacy in patients whose survival allows it and minimize overuse among patients with expected short survival. Clinician prediction has been shown to overestimate the length of survival in repeated studies. Prognostic indices can provide assistance with estimations of survival length and may help to guide treatment decisions regarding palliative radiotherapy in patients with potentially short survival times. This review explores the recent studies of radiotherapy near the end of life, examines general prognostic models for patients with advanced cancer, describes specific clinical circumstances when radiotherapy may and may not be beneficial, and addresses open questions for future research to help clarify when palliative radiotherapy may be effective near the end of life.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Inadequacy of Palliative Training in the Medical School Curriculum.

This report examines the literature on palliative training in the current medical school curriculum. A literature search was conducted to identify relevant articles. Physicians and medical students both report feeling that their training in end-of-life care and in palliative issues is lacking. The literature expresses concerns about the varied and non-uniform approach to palliative care training across medical schools. The authors recommend the development of more palliative training assessment tools in order to aid in the standardization of curriculum involving end-of-life care. In addition, increased exposure to dying patients will aid students in building comfort with palliative care issues. Such a goal may be accomplished through required clerkships or other similar programs.

Radiation therapy in the last month of life.

AIM: We sought to survey a large, multi-center patient sample to better characterize/quantify RT utilization at the end of life. BACKGROUND: Few objective data exist for radiation therapy (RT) delivery at end of life (EOL). MATERIALS AND METHODS: Data were retrieved for all patients receiving RT in calendar year 2010 in the Department of Radiation Oncology at Indiana University (IU) and Howard University (HU) hospitals. Specific attention was made of the group of patients receiving RT in the last 30 days of life. RESULTS: A total of 852 patients received all or part of their RT during 2010 (HU: 139, IU: 713). At time of analysis in early 2012, 179 patients had died (21%). Fifty-four patients (6.3% of total; 30% of expired patients) died within 30 days of receiving their last treatment. Twenty patients (2.3% of total; 11.2% of expired patients) received RT within their last week of life. For both sites, the median time until death from completion of therapy was 12.5 days (range 2-30 days). CONCLUSIONS: Radiation in the last month of life is likely to provide minimal palliation or survival benefit. This, coupled with the financial implications, time investment, and physical costs, suggests that physicians and patients should more strongly consider hospice, and minimize duration of palliative RT courses as far as possible. As with chemotherapy, RT utilization at EOL should be considered for collection as an overuse metric.

Whole brain radiotherapy for poor prognosis patients with brain metastases: predictably poor results.

BACKGROUND: Patients with brain metastases from solid tumors can be subdivided by characteristics into separate prognostic groups, such as the Radiation Therapy Oncology Group's Recursive Partitioning Analysis (RPA) or the Graded Prognostic Assessment (GPA). At our institution, patients falling into the poorest prognostic groups are often treated with whole brain radiotherapy (WBRT). OBJECTIVE: To determine if observed survival of poor prognosis patients treated with WBRT for brain metastases at our institution matches the survival predicted by RPA and GPA prognostic indices. METHODS: The charts of 101 consecutive patients with newly diagnosed brain metastases from solid tumors who received WBRT were retrospectively reviewed. We calculated each patient's RPA and GPA and compiled treatment and survival data. Observed median survival was compared to that predicted by the RPA and GPA prognostic indices. RESULTS: RPA III patients (n = 25) had a median survival of 2.4 months in our study. GPA 0.0-1.0 patients (n = 35) had a median survival of 2.4 months in our study. These values did not vary significantly from those predicted by the respective indices. LIMITATIONS: This is a retrospective analysis and subject to selection bias. CONCLUSION: Given the delivery time for WBRT and the potential side effects associated with the treatment, the predictably short overall survival in poor prognosis patients calls into question the value of WBRT in this patient subgroup.

International radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting.

PURPOSE: This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV). METHODS: Radiation oncology trainees who were members of the national radiation oncology associations of the USA, Canada, Netherlands, Australia, New Zealand, France, Spain and Singapore completed a Web-based survey. Respondents estimated the risks of nausea and vomiting associated with six standardised radiotherapy-only clinical case vignettes modelled after international anti-emetic guidelines and then committed to prophylactic, rescue or no therapy as an initial management approach for each case. RESULTS: One hundred and seventy-six trainees from 11 countries responded. Only 28 % were aware of any anti-emetic guideline. In general, risk estimates and management approaches for the high-risk and minimal risk cases varied less and were more in line with guideline standards than were estimates and approaches for the moderate- and low-risk cases. Prophylactic therapy was the most common approach for the high-risk and a moderate-risk case (83 and 71 % of respondents respectively), while rescue therapy was the most common approach for a second moderate-risk case (69 %), two low-risk cases (69 and 76 %) and a minimal risk case (68 %). A serotonin receptor antagonist was the most commonly recommended prophylactic agent. On multivariate analysis, a higher estimated risk of nausea predicted for recommending prophylactic therapy, and a lower estimated risk of nausea predicted for recommending rescue therapy. CONCLUSIONS: Radiation oncology trainee risk estimates and recommended management approaches for RINV clinical case vignettes varied and matched guideline standards more often for high-risk and minimal risk cases than for moderate- and low-risk cases. Risk estimates of nausea specifically were strong predictors of management decisions.

Appropriateness of the 30-day expected mortality metric in palliative radiation treatment: a narrative review.

BACKGROUND AND OBJECTIVE: The 30-day expected mortality rate is frequently used as a metric to determine which patients benefit from palliative radiation treatment (RT). We conducted a narrative review to examine whether its use as a metric might be appropriate for patient selection. METHODS: A literature review was conducted to identify relevant studies that highlight the benefits of palliative RT in timely symptom management among patients with a poor performance status, the accuracy of predicting survival near the end of life and ways to speed up the process of RT administration through rapid response clinics. KEY CONTENT AND FINDINGS: Several trials have demonstrated substantial response rates for pain and/or bleeding by four weeks and sometimes within the first two weeks after RT. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated Rapid Access Palliative RT (RAPRT) clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. CONCLUSIONS: Single-fraction palliative RT should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. We discourage the routine use of the 30-day mortality as the only metric to decide whether to offer RT. More common implementation of RAPRT clinics could result in a significant benefit for patients of all life expectancies, but particularly those having short ones.

A critical appraisal of the four systematic reviews and meta-analysis on stereotactic body radiation therapy versus external beam radiotherapy for painful bone metastases and where we go from here.

Radiotherapy is an important treatment modality for pain control in patients with bone metastases. Stereotactic body radiation therapy (SBRT), which allows delivering a much higher dose per fraction while sparing critical structures compared to conventional external beam radiotherapy (cEBRT), has become more widely used, especially in the oligometastatic setting. Randomized controlled trials (RCTs) comparing the pain response rate of SBRT and cEBRT for bone metastases have shown conflicting results, as have four recent systematic reviews with meta-analyses of these trials. Possible reasons for the different outcomes between these reviews include differences in methodology, which trials were included, and the endpoints examined and how they were defined. We suggest ways to improve analysis of these RCTs, particularly performing an individual patient-level meta-analysis since the trials included heterogeneous populations. The results of such studies will help guide future investigations needed to validate patient selection criteria, optimize SBRT dose schedules, include additional endpoints (such as the time to onset of pain response, durability of pain response, quality of life (QOL), and side effects of SBRT), and better assess the cost-effectiveness and trade-offs of SBRT compared to cEBRT. An international Delphi consensus to guide selection of optimal candidates for SBRT is warranted before more prospective data is available.

The role of radiation therapy in controlling painful bone metastases.

The management of painful bone metastases requires multidisciplinary care, with external beam radiation therapy (EBRT) providing relief that is effective and time efficient. Patients with bone metastases may require interventions including surgical decompression, osteoclast inhibitors, radiopharmaceuticals, and kyphoplasty or vertebroplasty, though EBRT should be included in the care of most of these patients, as well. Recent treatment-guideline publications for bone metastases greatly define the appropriate use of EBRT for this patient group, and they create a means by which treatment approaches may serve as quality measures of radiotherapy departments.

Why oncologists should refer patients earlier for hospice care.

The majority of patients with advanced malignancy die with a predictable disease trajectory. Increasing use of chemotherapy and radiotherapy near the end of life has not changed that trajectory. For adults with advanced solid tumors, the period from becoming symptomatic to death of the patient is 4 to 6 weeks. Poor performance status is still the most important prognostic factor, among others that have been described. The data are now in; hospice care is the best standard of care for cancer patients, it is not an alternative to standard care. Payers for high-quality cancer care will expect referral with an interval of care--generally on the order of 4 to 6 weeks of enrollment--as a measure of quality cancer care given by the oncologist. In this article, prognostic data are summarized and a suggested approach for discussing hospice enrollment with patients is presented.

Palliative radiotherapy: history, recent advances, and future directions.

Radiotherapy has been used to palliate cancer symptoms since shortly after the time that X rays were discovered late in the 1800's. The 20th century witnessed improvements in treatment planning and delivery that permitted radiotherapy to serve as a successful, timely, and cost-efficient palliative intervention. Palliative radiation oncology has risen to the level of its own subspecialty, as evidenced by the formation of palliative radiation oncology clinical services and dedicated palliative radiotherapy guidelines, while additional changes have begun to alter the very definition and goals of palliative radiotherapy. Local treatment may now be offered with dual goals of symptom relief and the potential for increased disease-free or overall survival. While these new directions show great promise, novel strategies must be formulated to manage the increased complexity, workload, and cost of these approaches.

Update of the systematic review of palliative radiation therapy fractionation for bone metastases.

PURPOSE: Radiation therapy is an effective modality for pain management of symptomatic bone metastases. We update the previous meta-analyses of randomized trials comparing single fraction to multiple fractions of radiation therapy in patients with uncomplicated bone metastases. METHODS: A literature search was conducted in Ovid Medline, Embase, and Cochrane Central Register. Ten new randomized trials were identified since 2010, five with adequate and appropriate data for inclusion, resulting in a total of 29 trials that were analyzed. Forest plots based on each study's odds ratios were computed using a random effects model and the Mantel-Haenszel statistic. RESULTS: In intention-to-treat analysis, the overall response rate was similar in patients for single fraction treatments (61%; 1867/3059) and those for multiple fraction treatments (62%; 1890/3040). Similarly, complete response rates were nearly identical in both groups (23% vs 24%, respectively). Re-treatment was significantly more frequent in the single fraction treatment arm, with 20% receiving additional treatment to the same site versus 8% in the multiple fraction treatment arm (p < 0.01). No significant difference was seen in the risk of pathological fracture at the treatment site, rate of spinal cord compression at the index site, or in the rate of acute toxicity. CONCLUSION: Single fraction and multiple fraction radiation treatment regimens continue to demonstrate similar outcomes in pain control and toxicities, but re-treatment is more common for single fraction treatment patients.

Management of metastatic spinal cord compression among Veterans Health Administration radiation oncologists.

BACKGROUND: Optimal management of metastatic spinal cord compression (MSCC) improves functional outcomes in patients with metastatic disease. This survey study evaluated management of MSCC by Veterans Health Administration (VHA) radiation oncologists (ROs), to determine whether management of MSCC correlates with American College of Radiology (ACR) guidelines, and to compare times to initiation of treatment between surgery and radiotherapy (RT). METHODS: Surveys emailed to 79 VHA ROs included questions on steroid use, surgical care, palliative care, fractionation of irradiation, re-irradiation, and management of common MSCC case scenarios. Follow-up phone calls were made to encourage survey participation. Descriptive statistics and chi-square testing were done to show significant associations. RESULTS: The survey yielded an 81.0% response rate; 79.4% of ROs had read the ACR Appropriateness Criteria® Spinal Bone Metastases. The majority (87.3%) prefer 30 Gy/10 fractions for MSCC, and all respondents recommend steroid therapy in conjunction with RT. When used, RT was more often initiated within 24 hours than was neurosurgery (83.9% vs. 34.5%, P<0.001). All ROs report use of palliative care services. Re-irradiation is given by 66.1%: 30.7% with stereotactic body radiation therapy (SBRT), 17.7% using intensity modulated radiation therapy (IMRT), and 17.7% using conventional RT. For the case scenarios, most respondents' (>75%) management concurred with ACR guidelines. CONCLUSIONS: The majority of VHA ROs are familiar with the ACR Appropriateness Criteria® Spinal Bone Metastases and practice accordingly. Treatment within 24 hours is more likely when RT is the primary modality compared to when surgical decompression precedes RT.

Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123.

OBJECTIVES: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. MATERIALS AND METHODS: Eligible patients included stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. RESULTS: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. CONCLUSIONS: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline.

PURPOSE: The purpose is to provide an update the Bone Metastases Guideline published in 2011 based on evidence complemented by expert opinion. The update will discuss new high-quality literature for the 8 key questions from the original guideline and implications for practice. METHODS AND MATERIALS: A systematic PubMed search from the last date included in the original Guideline yielded 414 relevant articles. Ultimately, 20 randomized controlled trials, 32 prospective nonrandomized studies, and 4 meta-analyses/pooled analyses were selected and abstracted into evidence tables. The authors synthesized the evidence and reached consensus on the included recommendations. RESULTS: Available literature continues to support pain relief equivalency between single and multiple fraction regimens for bone metastases. High-quality data confirm single fraction radiation therapy may be delivered to spine lesions with acceptable late toxicity. One prospective, randomized trial confirms both peripheral and spine-based painful metastases can be successfully and safely palliated with retreatment for recurrence pain with adherence to published dosing constraints. Advanced radiation therapy techniques such as stereotactic body radiation therapy lack high-quality data, leading the panel to favor its use on a clinical trial or when results will be collected in a registry. The panel's conclusion remains that surgery, radionuclides, bisphosphonates, and kyphoplasty/vertebroplasty do not obviate the need for external beam radiation therapy. CONCLUSION: Updated data analysis confirms that radiation therapy provides excellent palliation for painful bone metastases and that retreatment is safe and effective. Although adherence to evidence-based medicine is critical, thorough expert radiation oncology physician judgment and discretion regarding number of fractions and advanced techniques are also essential to optimize outcomes when considering the patient's overall health, life expectancy, comorbidities, tumor biology, anatomy, previous treatment including prior radiation at or near current site of treatment, tumor and normal tissue response history to local and systemic therapies, and other factors related to the patient, tumor characteristics, or treatment.

Efficacy of single fraction conventional radiation therapy for painful uncomplicated bone metastases: a systematic review and meta-analysis.

BACKGROUND: Single fraction radiotherapy (SFRT) and multiple fraction radiotherapy (MFRT) are effective for painful uncomplicated bone metastases and have been shown to be of similar efficacy. The optimal conventional external beam SFRT dose for maximum pain relief remains uncertain. The aim of this systematic review was to comprehensively review and synthesize overall pain response rates by dose. METHODS: A literature search was conducted in Ovid MEDLINE(R) (1946 to June 2016 week 3), Embase Classic & Embase (1947 to 2016 week 26) and Cochrane Central Register of Controlled Trials (May 2016) using keywords such as bone metastases, radiotherapy and single fraction (SF). RESULTS: The 635 results from the search were screened, and ultimately 27 were included for quantitative synthesis. The review indicated that 10 and 6 Gy may produce superior overall response (OR) and complete response (CR) rates compared to 8 Gy, and 6 Gy may result in better partial response (PR) than 8 Gy. However, only a few studies documented doses other than 8 Gy. In trials that directly compared 8 Gy to 4 Gy or 6 Gy, 8 Gy was deemed statistically superior. CONCLUSIONS: 8 Gy SFRT was the most commonly administered dose for palliation of bone metastases supporting its efficacy and safety. Future studies should explore the efficacy of 10 Gy while minimizing its side effects.

Does Graded Prognostic Assessment outperform Recursive Partitioning Analysis in patients with moderate prognosis brain metastases?

AIM: To compare the clinical utility of the Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) in predicting outcomes for moderate prognosis patients with brain metastases. METHODS & MATERIALS: We reviewed 101 whole brain radiotherapy cases. RPA and GPA were calculated. Overall survival was compared. RESULTS: Sixty-eight patients had moderate prognosis. RPA patient characteristics for increased death hazard were ≤10 WBRT fractions or no surgery/radiosurgery. GPA patients had increased death risk with no surgery/radiosurgery or lower Karnofsky Performance Status. CONCLUSION: The indices have similar predicted survival. Patients scored by RPA with longer radiation schedules had longer survival; patients scored by GPA did not. This indicates GPA is more clinically useful, leaving less room for subjective treatment choices.

The Availability of Advanced Radiation Oncology Technology within the Veterans Health Administration Radiation Oncology Centers.

Radiation oncologists were surveyed to determine how accessible advanced radiation delivery modalities are within the VHA.