Edward Chow

Palliative Radiotherapy Trials for Bone Metastases: A Systematic Review

PURPOSE The objective is to update previous meta-analyses with a systematic review of randomized palliative radiotherapy (RT) trials comparing single fractions (SFs) versus multiple fractions (MFs). METHODS The analysis includes all published reports from randomized trials comparing SF or MF schedules for the treatment of painful bone metastases with localized RT. A systematic review was performed using the random-effects model with Review Manager version 4.1 (Cochrane Collaboration, Oxford, UK). The odds ratio and 95% CI were calculated for each trial and presented in a forest plot. RESULTS A total of 16 randomized trials from 1986 onward were identified. For intention-to-treat patients, the overall response (OR) rates for pain were similar for SF at 1,468 (58%) of 2,513 patients and MF RT at 1,466 (59%) of 2,487 patients. The complete response (CR) rates for pain were 23% (545 of 2,375 patients) for SF and 24% (558 of 2,351 patients) for MF RT. No significant differences were found in response rates. Trends showing an increased risk for SF RT arm patients in terms of pathological fractures and spinal cord compressions were observed, but neither were statistically significant (P = .75 and P = .13, respectively). The likelihood of re-treatment was 2.5-fold higher (95% CI, 1.76 to 3.56) in SF RT arm patients (P < .00001). Repeated analysis of these end points, excluding dropout patients, did not alter the conclusions. Generally, no significant differences with respect to acute toxicities were observed between the arms. CONCLUSION No significant differences in the arms were observed for overall and CR rates in both intention-to-treat and assessable patients. However, a significantly higher re-treatment rate with SFs was evident.

Palliative radiotherapy for bone metastases: An ASTRO evidence-based guideline

PURPOSE To present guidance for patients and physicians regarding the use of radiotherapy in the treatment of bone metastases according to current published evidence and complemented by expert opinion. METHODS AND MATERIALS A systematic search of the National Library of Medicines PubMed database between 1998 and 2009 yielded 4,287 candidate original research articles potentially applicable to radiotherapy for bone metastases. A Task Force composed of all authors synthesized the published evidence and reached a consensus regarding the recommendations contained herein. RESULTS The Task Force concluded that external beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases. Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases. The evidence for the safety and efficacy of repeat treatment to previously irradiated areas of peripheral bone metastases for pain was derived from both prospective studies and retrospective data, and it can be safe and effective. The use of stereotactic body radiotherapy holds theoretical promise in the treatment of new or recurrent spine lesions, although the Task Force recommended that its use be limited to highly selected patients and preferably within a prospective trial. Surgical decompression and postoperative radiotherapy is recommended for spinal cord compression or spinal instability in highly selected patients with sufficient performance status and life expectancy. The use of bisphosphonates, radionuclides, vertebroplasty, and kyphoplasty for the treatment or prevention of cancer-related symptoms does not obviate the need for external beam radiotherapy in appropriate patients. CONCLUSIONS Radiotherapy is a successful and time efficient method by which to palliate pain and/or prevent the morbidity of bone metastases. This Guideline reviews the available data to define its proper use and provide consensus views concerning contemporary controversies or unanswered questions that warrant prospective trial evaluation.

International consensus on palliative radiotherapy endpoints for future clinical trials in bone metastases

Abstract Purpose : To reach a consensus on a set of optimal endpoint measurements for future external beam radiotherapy trials in bone metastases. Methods : An International Bone Metastases Consensus Working Party invited principal investigators and individuals with a recognized interest in bone metastases to participate in the two surveys and a panel meeting on their preference of choice of optimal endpoints. Results : Consensus has been reached on the following: (a) eligibility criteria for future trials; (b) pain and analgesic assessments; (c) radiation techniques; (d) follow-up and timing of assessments; (e) parameters at follow-up; (f) endpoints; (g) re-irradiation; and (h) statistical analysis. Conclusions : Based on the available literature and the clinical experience of the working party members, an acceptable set of endpoints has been agreed upon for future clinical trials to promote consistency in reporting. It is intended that the consensus will be re-examined every 5 years. Areas of further research were identified.

Palliative Thoracic Radiotherapy for Lung Cancer: A Systematic Review

PURPOSE The optimal dose of radiotherapy (RT) to palliate symptomatic advanced lung cancer is unclear. We systematically reviewed randomized controlled trials (RCTs) of palliative thoracic RT. METHODS RCTs comparing two or more dose fractionation schedules were reviewed using the random-effects model of a freely available information management system. The relative risk and 95% CI for each outcome were presented in Forrest plots. Exploratory analysis comparing dose schedules after conversion to the time-adjusted biologically equivalent dose (BED) was performed to investigate for a dose-response relationship. RESULTS A total of 13 RCTs involving 3,473 randomly assigned patients were identified. Outcomes included symptom palliation, overall survival, toxicity, and reirradiation rate. For symptom control in assessable patients, lower-dose (LD) RT was comparable with higher-dose (HD), except for the total symptom score (TSS): 65.4% of LD and 77.1% of HD patients had improved TSS (P = .003). Greater likelihood of symptom improvement was seen with schedules of 35 Gy(10) versus lower BED. At 1 year after HD and LD RT, 26.5% versus 21.7% of patients were alive, respectively (P = .002). Sensitivity analysis suggests this survival improvement was seen with 35 Gy(10) BED schedules compared with LDs. Physician-assessed dysphagia was significantly greater in the HD arm (20.5% v 14.9%; P = .01), and the likelihood of reirradiation was 1.2-fold higher after LD RT. CONCLUSION No significant differences were observed for specific symptom-control end points, although improvement in survival favored HD RT. Consideration of palliative thoracic RT of at least 35 Gy(10) BED may therefore be warranted, but must be weighed against increased toxicity and greater time investment.

International Patterns of Practice in Palliative Radiotherapy for Painful Bone Metastases: Evidence-Based Practice?

PURPOSE Multiple randomized controlled trials have demonstrated the equivalence of multifraction and single-fraction (SF) radiotherapy for the palliation of painful bone metastases (BM). However, according to previous surveys, SF schedules remain underused. The objectives of this study were to determine the current patterns of practice internationally and to investigate the factors influencing this practice. METHODS AND MATERIALS The members of three global radiation oncology professional organizations (American Society for Radiology Oncology [ASTRO], Canadian Association of Radiation Oncology [CARO], Royal Australian and New Zealand College of Radiologists) completed an Internet-based survey. The respondents described what radiotherapy dose fractionation they would recommend for 5 hypothetical cases describing patients with single or multiple painful BMs from breast, lung, or prostate cancer. Radiation oncologists rated the importance of patient, tumor, institution, and treatment factors, and descriptive statistics were compiled. The chi-square test was used for categorical variables and the Student t test for continuous variables. Logistic regression analysis identified predictors of the use of SF radiotherapy. RESULTS A total of 962 respondents, three-quarters ASTRO members, described 101 different dose schedules in common use (range, 3 Gy/1 fraction to 60 Gy/20 fractions). The median dose overall was 30 Gy/10 fractions. SF schedules were used the least often by ASTRO members practicing in the United States and most often by CARO members. Case, membership affiliation, country of training, location of practice, and practice type were independently predictive of the use of SF. The principal factors considered when prescribing were prognosis, risk of spinal cord compression, and performance status. CONCLUSION Despite abundant evidence, most radiation oncologists continue to prescribe multifraction schedules for patients who fit the eligibility criteria of previous randomized controlled trials. Our results have confirmed a delay in the incorporation of evidence into practice for palliative radiotherapy for painful bone metastases.

Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial

BACKGROUND Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. We aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. METHODS We did a multicentre, non-blinded, randomised, controlled trial in nine countries worldwide. We enrolled patients 18 years or older who had radiologically confirmed, painful (ie, pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimisation to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment centre. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. FINDINGS Between Jan 7, 2004, and May 24, 2012, we randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomisation, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0·21; response difference of 4·00% [upper limit of the 95% CI 9·2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0·17; response difference 6·00% [upper limit of the 95% CI 13·2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs 229 [66%] of 349 assessable patients who received 20 Gy; p=0·011) and diarrhoea (81 [23%] of 357 vs 108 [31%] of 349; p=0·018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1·54, 95% CI 0·85-2·75; p=0·15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3·54, 95% CI 0·73-17·15; p=0·094). INTERPRETATION In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist. FUNDING Canadian Cancer Society Research Institute, US National Cancer Institute, Cancer Council Australia, Royal Adelaide Hospital, Dutch Cancer Society, and Assistance Publique-Hôpitaux de Paris.

Impact of skeletal complications on patients’ quality of life, mobility, and functional independence

IntroductionSkeletal-related events (SREs) from malignant bone disease cause considerable morbidity and can dramatically reduce patients’ quality of life.DiscussionPathologic fractures often require surgical intervention and palliative radiotherapy. Thus, patients suffer impaired mobility, loss of functional independence, and diminished health-related quality of life (HRQOL). Bisphosphonates can delay the onset and reduce the incidence of SREs and have become the standard of care for the treatment of malignant bone disease; however, minimal information on the effects of bisphosphonate treatment on HRQOL is available. Targeted HRQOL assessments for patients with malignant bone disease are currently under development and are discussed herein.

Quality of life in surgical treatment of metastatic spine disease

Study Design. Overall quality of life after surgical management of metastatic disease of the spine was prospectively assessed using a validated global health status quality-of-life instrument—the Edmonton Symptom Assessment Scale. Objectives. To prospectively evaluate the efficacy of surgery in patients with metastatic spinal disease with respect to quality of life. Summary of Background Data. Management of spinal metastases is palliative and is aimed at improving quality of life at an acceptable risk. Although previous studies have evaluated physical outcomes, improvements in pain, and neurologic function after surgery, a multidimensional assessment of quality of life is more relevant in the palliative patient. Methods. Twenty-five consecutive patients undergoing surgery for spinal metastases were prospectively evaluated. Pre- and postoperative assessments were performed using the Edmonton Symptom Assessment Scale. The surgical procedure consisted of decompression and instrumented stabilization. Results. After surgery, the largest improvement was noted in the domain of pain (P < 0.00001). There were also significant improvements noted in the domains of tiredness (P = 0.004), nausea (P = 0.01), anxiety (P = 0.006), drowsiness (P = 0.044), appetite (P = 0.02), and well-being (P = 0.004). Conclusions. The current study demonstrates that in the appropriate patient, surgical management brings about a positive effect on the overall quality of life in patients with spinal metastases. The greatest benefit occurred in the reduction of a patient’s level of pain.

Palliation of bone metastases: a survey of patterns of practice among Canadian radiation oncologists☆

BACKGROUND Palliative radiotherapy constitutes nearly 50% of the workload in radiotherapy. Surveys on the patterns of practice in radiotherapy have been published from North America and Europe. Our objective was to determine the current pattern of practice of radiation oncologists in Canada for the palliation of bone metastases. METHOD A survey was sent to 300 practicing radiation oncologists in Canada. Five case scenarios were presented. The first three were patients with a single symptomatic site: breast cancer patient with pelvic metastasis, lung cancer male with metastasis to L3 and L1, respectively. The last two were breast and prostate cancer patients with multiple symptomatic bone metastases. RESULTS A total of 172 questionnaires were returned (57%) for a total of 860 responses. For the three cases with a single painful bone metastasis, over 98% would prescribe radiotherapy. The doses ranged from a single 8 to 30 Gy in ten fractions. Of the 172 respondents, 117 (68%) would use the same dose fractionation for all three cases, suggesting that they had a standard dose fractionation for palliative radiotherapy. The most common dose fractionation was 20 Gy in five fractions used by 84/117 (72%), and 8 Gy in one fraction by 19/117 (16%). In all five case scenarios, 81% would use a short course of radiotherapy (single 8 Gy, 17%; 20 Gy in five fractions, 64%), while 10% would prescribe 30 Gy in ten fractions. For the two cases with diffuse symptomatic bone metastases, half body irradiation (HBI) and radionuclides were recommended more frequently in prostate cancer than in breast cancer (46/172 vs. 4/172, P<0. 0001; and 93/172 vs. 10/172, P<0.0001, respectively). Strontium was the most commonly recommended radionuclide (98/103=95%). Since systemic radionuclides are not readily available in our health care system, 41/98 (42%) of radiation oncologists who would recommend strontium were not familiar with the dose. Bisphosphonates were recommended more frequently in breast cancer than in prostate cancer 13/172 (8%) vs. 1/172 (0.6%), P=0.001. CONCLUSION Local field external radiotherapy remains the mainstay of therapy, and the most common fractionation for bone metastases in Canada is 20 Gy in five fractions compared with 30 Gy in ten fractions in the US. Despite randomized trials showing similar results for single compared with fractionated radiotherapy, the majority of us still advocate five fractions. The frequency of employing a single fractionation has not changed since the last national survey in 1992. Nearly 70% use a standard dose fractionation to palliate localized painful metastasis by radiotherapy, independent of the site of involvement or tumor type. The pattern of practice of palliative radiotherapy for bone metastases in Canada is different to that reported previously from the US. The reasons why the results of randomized studies on bone metastases have no impact on the patterns of practice are worth exploring.

A predictive model for survival in metastatic cancer patients attending an outpatient palliative radiotherapy clinic

PURPOSE To develop a predictive model for survival from the time of presentation in an outpatient palliative radiotherapy clinic. METHODS AND MATERIALS Sixteen factors were analyzed prospectively in 395 patients seen in a dedicated palliative radiotherapy clinic in a large tertiary cancer center using Coxs proportional hazards regression model. RESULTS Six prognostic factors had a statistically significant impact on survival, as follows: primary cancer site, site of metastases, Karnofsky performance score (KPS), and fatigue, appetite, and shortness of breath scores from the modified Edmonton Symptom Assessment Scale. Risk group stratification was performed (1) by assigning weights to the prognostic factors based on their levels of significance, and (2) by the number of risk factors present. The weighting method provided a Survival Prediction Score (SPS), ranging from 0 to 32. The survival probability at 3, 6, and 12 months was 83%, 70%, and 51%, respectively, for patients with SPS <or=13 (n = 133); 67%, 41%, and 20% for patients with SPS 14-19 (n = 129); and 36%, 18%, and 4% for patients with SPS >or=20 (n = 133) (p < 0.0001). Corresponding survival probabilities based on number of risk factors were as follows: 85%, 72%, and 52% (<or=3 risk factors)(n = 98); 68%, 47%, and 24% (4 risk factors)(n = 117); and 46%, 24%, and 11% (>or=5 factors)(n = 180)(p < 0.0001). CONCLUSION Clinical prognostic factors can be used to predict prognosis among patients attending a palliative radiotherapy clinic. If validated in an independent series of patients, the model can be used to guide clinical decisions, plan supportive services, and allocate resource use.