Summary 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.
Summary Background Pain flare occurs after palliative radiotherapy, and dexamethasone has shown potential for prevention of such flare. We aimed to compare the efficacy of dexamethasone with that of ...placebo in terms of reduction of incidence of pain flare. Methods In this double-blind, randomised, placebo-controlled phase 3 trial, patients from 23 Canadian centres were randomly allocated (1:1) with a web-based system and minimisation algorithm to receive either two 4 mg dexamethasone tablets or two placebo tablets taken orally at least 1 h before the start of radiation treatment (a single 8 Gy dose to bone metastases; day 0) and then every day for 4 days after radiotherapy (days 1–4). Patients were eligible if they had a non-haematological malignancy and bone metastasis (or metastases) corresponding to the clinically painful area or areas. Patients reported their worst pain scores and opioid analgesic intake before treatment and daily for 10 days after radiation treatment. They completed the European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C15-PAL, the bone metastases module (EORTC QLQ-BM22), and the Dexamethasone Symptom Questionnaire at baseline, and at days 10 and 42 after radiation treatment. Pain flare was defined as at least a two-point increase on a scale of 0–10 in the worst pain score with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in the worst pain score from days 0–10, followed by a return to baseline levels or below. Primary analysis of incidence of pain flare was by intention-to-treat (patients with missing primary data were classified as having pain flare). This study is registered with ClinicalTrials.gov , number NCT01248585 , and is completed. Findings Between May 30, 2011, and Dec 11, 2014, 298 patients were enrolled. 39 (26%) of 148 patients randomly allocated to the dexamethasone group and 53 (35%) of 150 patients in the placebo group had a pain flare (difference 8·9%, lower 95% confidence bound 0·0, one-sided p=0·05). Two grade 3 and one grade 4 biochemical hyperglycaemic events occurred in the dexamethasone group (without known clinical effects) compared with none in the placebo group. The most common adverse events were bone pain (61 41% of 147 vs 68 48% of 143), fatigue (58 39% of 147 vs 49 34% of 143), constipation (47 32% of 147 vs 37 26% of 143), and nausea (34 23% of 147 vs 34 24% of 143), most of which were mild grade 1 or 2. Interpretation Dexamethasone reduces radiation-induced pain flare in the treatment of painful bone metastases. Funding The NCIC CTG's programmatic grant from the Canadian Cancer Society Research Institute.
To estimate the prevalence of pain with neuropathic features among patients with metastatic bone pain and to assess differences between patients with and without neuropathic features by pain ...severity, functional interference, and quality-of-life (QOL) measures.
A prospective cross-sectional survey of consecutive patients with symptomatic bone metastases was conducted between December 2006 and March 2008 at a comprehensive cancer center. Patients completed the Brief Pain Inventory (BPI), the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). Statistical associations between pain with neuropathic features and other measures were explored.
Ninety-eight patients were enrolled. Seventeen percent of patients (95% CI, 10% to 24%) had positive S-LANSS scores suggesting pain with neuropathic features. Mean worst pain and mean interference scores were 7.2 (standard deviation SD, 2.0) and 5.8 (SD, 2.5), respectively. EORTC QLQ-C30 global QOL, function, and symptom scores were 42 (SD, 24), 52 (SD, 20), and 46 (SD, 17), respectively. Patients with neuropathic features had a higher BPI worst pain score than patients without neuropathic features (8.3 v 7.0, respectively; P = .016). Corticosteroid use, oral morphine equivalent dosing, and site of bone pain were not associated with neuropathic features.
Some patients with bone metastases manifest bone pain with distinguishable neuropathic features, and these patients reported greater pain intensity. Additional work is required to validate the S-LANSS against clinical criteria for neuropathic pain in this context and to explore the unmet pain management needs in this population.
Many studies that found improved quality of life (QOL) after radiotherapy of bone metastases have small sample sizes and do not use specific questionnaires. How soon after radiotherapy one can expect ...an improvement in QOL is unknown.
To investigate QOL at days 10 and 42 after radiotherapy with a bone metastases-specific QOL tool.
In this secondary analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23, a double-blind randomized clinical trial that investigated dexamethasone for the prophylaxis of pain flare after radiotherapy, patients were accrued from 23 Canadian centers from May 30, 2011, to December 11, 2014, and were followed up for 42 days after treatment. Participants referred for radiotherapy for bone metastases were required to have a pain score at the site(s) of treatment of at least 2 (range, 0-10).
Patients were treated with a single 8-Gy radiotherapy dose for 1 or 2 bone metastases.
Patients reported their worst pain score and analgesic intake at baseline and days 10 and 42 after treatment. Pain response was assessed with International Bone Metastases Consensus Endpoint Definitions. Self-reported QOL was completed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Bone Metastases Module (QLQ-BM22) and the European Organisation for Research and Treatment of Cancer Quality of Life Core 15 Palliative (QLQ-C15-PAL) at the same time points.
A total of 298 patients were accrued (median age, 68.8 range, 32-94 years at day 10 and 68.0 range, 34-90 years at day 42). A total of 122 patients (40.9%) responded to radiotherapy at day 10 and 116 patients (38.9%) at day 42. At day 10, compared with nonresponders, patients with a pain response had a greater reduction in pain (mean reduction, 17.0 vs 1.8; P = .002) and pain characteristics (mean reduction, 12.8 vs 1.1; P = .002), as well as greater improvements in functional interference (mean increase, 11.6 vs 3.6; P = .01) and psychosocial aspects (mean increase, 1.2 points in responders vs mean decrease of 2.2 points in nonresponders, P = .04). Comparing changes in QOL from baseline to day 42, responders had significantly greater improvements in the physical (mean increase, 6.2 vs -9.0; P < .001), emotional (mean increase, 12.3 vs -5.5; P < .001), and global domains (mean increase, 10.3 vs -4.5; P < .001) of the QLQ-C15-PAL compared with nonresponders.
Forty percent of patients experienced pain reduction and better QOL at day 10 after radiotherapy with further improvements in QOL at day 42 in responders. A single 8-Gy radiotherapy dose for bone metastases should be offered to all patients, even those with poor survival.
clinicaltrials.gov Identifier: NCT01248585.
Purpose The EORTC QLQ-C30 and the Brief Pain Inventory (BPI) are validated tools for measuring quality of life (QOL) and the impact of pain in patients with advanced cancer. Interpretation of these ...instrument scores can be challenging and it is difficult to know what numerical changes translate to clinically significant impact in patients' lives. To address this issue, our study sought to establish the minimal clinically important differences (MCID) for these two instruments in a prospective cohort of patients with advanced cancer and painful bone metastases. Methods Both anchor-based and distribution-based methods were used to estimate the MCID scores from patients enrolled in a randomized phase III trial evaluating two different re-irradiation treatment schedules. For the anchor-based method, the global QOL item from the QLQ-C30 was chosen as the anchor. Spearman correlation coefficients were calculated for all items and only those items with moderate or better correlation (|r| ≥ 0.30) with the anchor were used for subsequent analysis. A 10-point difference in the global QOL score was used to classify improvement and deterioration, and the MCID scores were calculated for each of these categories. These results were compared with scores obtained by the distribution-method, which estimates the MCID purely from the statistical characteristics of the sample population. Results A total of 375 patients were included in this study with documented pain responses and completed QOT. questionnaires at 2 months. 9/14 items in the QLQ-C30 and 6/10 items in the BPI were found to have moderate or better correlation with the anchor. For deterioration, statistically significant MCID scores were found in all items of the QLQ-C30 and BPI. For improvement, statistically significant MCID scores were found in 7/9 items of the QLQ-C30 and 2/6 items of the BPI. The MCID scores for deterioration were uniformly higher than the MCIDs for improvement. Using the distribution-based method, there was good agreement between the 0.5 standard deviation (SD) values and anchor-based scores for deterioration. For improvement, there was less agreement and the anchor-based scores were lower than the 0.5 SD values obtained from the distribution-based method. Conclusion We present MCID scores for the QLQ-C30 and BPI instruments obtained from a large cohort of patients with advanced cancer undergoing re-irradiation for painful bone metastases. The results from this study were compared to other similar studies which showed larger MCID scores for improvement compared to deterioration. We hypothesize that disease trajectory and patient expectations are important factors in understanding the contrasting results. The results of this study can guide clinicians and researchers in the interpretation of these instruments.
Background
Aggressive medical management of cancer patients at the end of life (EOL) is an indicator of health services quality. We evaluated the variations in EOL cancer therapy utilization and in ...acute care hospital deaths across different types of cancer within the setting of a regionalized cancer program.
Methods
Intravenous chemotherapy and radiotherapy use within the last 14 and 30 days of life was identified through the Alberta Cancer Registry and then verified by chart review for cancer decedents residing within 50 km of the Tom Baker Cancer Centre between 2003 and 2010. Multivariable logistic regression was used to examine variations in outcomes of interest by cancer, adjusting for age and other factors in prespecified models.
Results
Of the 9863 decedents included in the study, 3.0 and 6.3 % received chemotherapy within the final 14 and 30 days of life, respectively. In multivariable model, breast, hematological, and gynecological cancers were at least 2.5 times more likely than other cancers to undergo EOL chemotherapy. Radiotherapy was given to 4.6 % of decedents within 14 days of death, but only 66 % (359/542 courses) were completed as prescribed. Acute care admission within 14 days of death was seen in 44 % of decedents and 34 % died in the hospital.
Conclusions
In our regional cancer program, the intensity of cancer therapies near the end of life varied considerably across different cancer types. Such variations may be unwarranted. A substantial proportion of cancer deaths occurred in the acute care setting. Greater efforts to integrate palliative care in outpatient cancer services are needed.
Purpose
Previous studies have determined optimal cut points (CPs) for the classification of pain severity as mild, moderate, or severe using only the Brief Pain Inventory (BPI) or the BPI in ...conjunction with a quality of life (QOL) tool. The purpose of our study was to determine the optimal CPs based on correlation with only QOL outcomes.
Methods
We conducted an analysis of 298 patients treated with radiation therapy for painful bone metastases on a phase III randomized trial. Prior to treatment, patients provided their worst pain score on a scale of 0 (no pain) to 10 (worst possible pain), as well as completed the European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Bone Metastases module (QLQ-BM22) and the EORTC QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL). Optimal CPs were determined to be those that yielded the largest
F
ratio for the between category effect on each subscale of the QLQ-BM22 and QLQ-C15-PAL using the multivariate analysis of variance (MANOVA).
Results
The two largest
F
ratios for Wilk’s
λ
, Pillai’s Trace, and Hotelling’s Trace were for CPs 5,6 and 5,7. Combining both, the optimal CPs to differentiate between mild, moderate, and severe pain were 5 and 7. Pain scores of 1–5, 6, and 7–10 were classified as mild, moderate, and severe, respectively. Patients with severe pain experienced greater functional interference and poorer QOL when compared to those with mild pain.
Conclusion
Our results suggest that, based on the impact of pain on QOL measures, pain scores should be classified as follows: 1–5 as mild pain, 6 as moderate pain, and 7–10 as severe pain. Optimal CPs vary depending on the type of outcome measurement used.
External beam radiotherapy (RT) is commonly indicated for the palliation of symptomatic bone metastases, but there is evidence of underutilization of this treatment modality in palliative care for ...cancer populations. This study was conducted to investigate factors that influenced the use of palliative RT services at a regional comprehensive cancer center.
A cohort of patients with radiographically confirmed bone metastases and first-time users of palliative RT between 2003 and 2005 was retrospectively reviewed from the time of initial diagnosis of bone metastases to death or last follow-up. Type of radiation treatment service provider used (rapid access or routine access) and patient-, tumor-, and treatment-related factors were analyzed for their influences on the number of treatment courses given over the duration of disease.
A total of 887 patients received 1,354 courses of palliative RT for bone metastases at a median interval of 4.0 months between courses. Thirty-three percent of patients required more than one RT course. Increased age and travel distance reduced the likelihood and number of treatment courses, while service through a rapid access clinic was independently associated with an increase in subsequent use of palliative RT.
A rapid access service model for palliative RT facilitated access to RT. Travel distance and other factors remained substantial barriers to use of palliative RT services. The pattern of practice suggests an unmet need for symptom control in patients with bone metastases.
Purpose
The objective of our study was to determine the optimal cut points for classification of pain scores as mild, moderate, and severe based on interference with function and quality of life ...(QOL).
Methods
We evaluated 822 patients who completed the Brief Pain Inventory (BPI) and/or the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30 (QLQ-C30) prior to receiving repeat radiation therapy for previously irradiated painful bone metastases. Optimal cut points for mild, moderate, and severe pain were determined by the MANOVA that yielded the largest
F
ratio for the between category effect on the seven interference items of BPI and the six functional domains of QOL (physical, role, emotional, cognitive, social functioning, and global QOL) as indicated by Pillai’s Trace, Wilk’s
λ
, and Hostelling’s Trace
F
statistics.
Results
For BPI and for QOL domains separately, the two largest
F
ratios for Wilk’s
λ
, Pillai’s Trace, and Hotelling’s Trace
F
statistics were from the cut points 4, 8 and 6, 8. When combining both, the optimal cut points were 4, 8 with 1–4 (mild), 5–8 (moderate), and 9–10 (severe). With this classification, the mean scores of all the seven interference items in BPI and the six functional domains were all highly statistically different. Patients with severe pain survived significantly shorter than those with mild and moderate pain (
p
< 0.0001).
Conclusion
Our analysis supports the classification of pain scores as follows: 1–4 as mild pain, 5–8 as moderate pain, and 9–10 as severe pain. This may facilitate conduct of future clinical trials.
Purpose Validated tools for evaluating quality of life (QOL) in patients with bone métastases include the EORTC QLQ-BM22 and QLQ-C15-PAL modules. A statistically significant difference in metric ...scores may not be clinically significant. To aid in their interpretation, we performed analyses to determine the minimal clinically important differences (MCID) for these QOL instruments. Methods Both anchor-based and distribution-based methods were used to determine the MCID among patients with bone métastases enrolled in a randomized phase III trial. For the anchor-based approach, overall QOL as measured by the QLQ-C15-PAL module was used as the anchor and only the subscales with moderate or better correlation were used for subsequent MCID analysis. In the anchor-based approach, patients were classified as improved, stable or deteriorated by the change in the overall QOL score from baseline to follow-up after 42 days. The MCID and confidence interval was then calculated for all subscales. In the distribution-based approach, the MCID was expressed as a proportion of the standard deviation and standard error measurement from the subscale score distribution. Results A total of 204 patients completed the questionnaires at baseline and follow-up. Only the dyspnea and insomnia subscales did not have at least moderate correlation with the overall QOL anchor. Using the anchorbased approach, 10/11 subscales had an MCID score significantly different than 0 for improvement and 3/11 subscales had a significant MCID score for deterioration. The magnitude of MCID scores was higher for improvement in comparison with deterioration. For improvement, the anchor-based approach showed good agreement with the distribution-based approach when using 0.5 SD as the MCID. However, there was greater lack of agreement between these approaches for deterioration. Conclusion We present the MCID scores for the EORTC QLQ-BM22 and QLQ-C15-PAL QOL instruments. The results of this study can guide clinicians in the interpretation of these instruments.
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