Patient Reported Outcomes After Radiation Therapy for Bone Metastases as a Function of Age: A Secondary Analysis of the NCIC CTG SC-Twenty-Three Randomized Trial.

PURPOSE: To explore the age difference in response and patient-reported outcomes in patients with cancer having bone metastases undergoing palliative radiotherapy. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life (QOL) Bone Metastases module (QLQ-BM22), EORTC QOL Core-15-Palliative (QLQ-C15-PAL), and Dexamethasone Symptom Questionnaire (DSQ) before a single 8-Gy radiation treatment, on days 10 and 42 after treatment. Patient demographics, performance status, analgesic consumption, BM22, C15, and DSQ were compared with multivariant analysis between patients under 75 years and 75 years and older. Multiple linear regression models were used to assess the differences between age-groups, adjusting for baseline demographics and primary disease sites. RESULTS: There were 298 patients (170 male) with 209 (70%) less than 75 years of age. Most common primary cancer sites include lung, prostate, and breast. At baseline, younger patients had better performance status, consumed more analgesic, and reported worse scores in nausea, insomnia, and functional interference, while older patients more commonly had prostate cancer. There were no significant differences in the incidence of radiation-induced pain flare; response to radiation; changes from baseline for BM22, C15-PAL; and DSQ, nor overall survival at day 42 between the 2 groups. Responders to radiation in the elderly group reported better improvement in physical and emotional domains when compared with nonresponders. CONCLUSIONS: In patients with cancer having bone metastases undergoing palliative radiotherapy, there was no significant difference in general with age in response to radiation and patient-reported outcomes. Palliative radiotherapy should be offered to elderly patients when needed.

Minimal clinically important differences in the EORTC QLQ-C30 and brief pain inventory in patients undergoing re-irradiation for painful bone metastases.

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 QOL 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.

Gender and age make no difference in the re-irradiation of painful bone metastases: A secondary analysis of the NCIC CTG SC.20 randomized trial.

BACKGROUND AND PURPOSE: Patient's gender and age may influence physicians in prescribing palliative radiotherapy. The purpose of this secondary analysis of the National Cancer Institute of Canada Clinical Trials Group Symptom Control Trial SC.20 was to explore the gender and age differences in pain and patient reported outcomes in cancer patients with bone metastases undergoing re-irradiation. MATERIALS AND METHODS: Response to radiation was evaluated using the International Bone Metastases Consensus Endpoint Definitions. Patients completed the Brief Pain Inventory (BPI) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (C30) before and 2 months after re-irradiation. RESULTS: A total of 847 patients were analyzed. At baseline, men had more dyspnea, and mild pain. Older patients consumed less analgesic. More women reported clinically significant improvement in mood and enjoyment of life in the BPI after radiation. Similarly, younger patients reported better improvement in enjoyment of life. There were no significant gender or age differences in overall survival, response to radiation, or in C30 scores at 2 months. CONCLUSION: Similar benefit in terms of pain relief was observed across all patient groups. Cancer patients with bone metastases should be offered palliative re-irradiation irrespective of gender or age. TRIAL REGISTRATION: NCT00080912; https://clinicaltrials.gov/ct2/show/NCT00080912.

Gender differences in pain and patient reported outcomes: a secondary analysis of the NCIC CTG SC. 23 randomized trial.

BACKGROUND: Gender differences may contribute to variations in disease presentations and health outcomes. To explore the gender difference in pain and patient reported outcomes in cancer patients with bone metastases undergoing palliative radiotherapy on the National Cancer Institute of Canada (NCIC) SC.23 randomized trial. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) bone metastases module (QLQ-BM22) and EORTC QOL Core-15-Palliative (QLQ-C15-PAL) before treatment and at days 10 and 42 after a single 8 Gy radiation treatment. Patient demographics, performance status, analgesic consumption, BM22 and C15 were compared between males and females using the 2-sample t-test for continuous variables or the Chi-squared test for categorical variables. Multiple linear regression models were used to check the difference between gender groups adjusting for the baseline demographics and primary disease sites. RESULTS: There were 298 patients (170 male, 128 female) with median age of 69 years. The most common primary cancer sites were lung, prostate and breast. At baseline, there were no differences in BM22 and C15 scores, except a worse nausea and vomiting score (P=0.03) in females on the C15. In patients with moderate baseline worst pain scores (WPS), females reported worse scores in painful sites of BM22. At day 42, there was no significant difference in response to radiotherapy. Among the responders, females reported better improvement in emotional aspect. CONCLUSIONS: In cancer patients with bone metastases undergoing palliative radiotherapy, the majority of symptom presentations, patient reported outcomes, and response to radiation was not significantly different between genders. TRIAL REGISTRATION: NCT01248585.

Genetic biomarkers associated with response to palliative radiotherapy in patients with painful bone metastases.

BACKGROUND: Palliative radiotherapy (RT) is effective in patients with painful bone metastases. Genetic factors may identify subgroup of patients who responded to RT. To identify DNA biomarkers associated with response to palliative RT. METHODS: Patients who received a single 8 Gy dose of RT for painful bone metastases were categorised into responders (n=36), non-responders (NR) (n=71). Saliva samples were sequenced to identify single-nucleotide variants (SNVs) in genes with known disease-causing variants from inflammation, radiation response, and DNA damage pathways. In univariate analysis, Cochran-Armitage trend tests were used to identify SNVs that associated with pain response (P<0.005), and the Penalized LASSO method with minimum Bayesian Information Criterion was used to identify multi-SNVs that jointly predict pain response to RT. The corresponding estimated effect of the multi-SNVs were used to drive the prognostic score for each patient. Based on it, patients were divided into 3 equal size risk groups. RESULTS: Forty-one significant variants were identified in univariate analysis. Multivariable analysis selected 14 variants to generate prognostic scores, adjusting for gender and primary cancer site. Eighty-nine percent of patients in the high prognostic group responded to palliative radiation therapy (P=0.0001). Estimated effect sizes of the variants ranged from 0.108-2.551. The most statistically significant variant was a deletion at position 111992032 in the ataxin gene ATXN2 (P=0.0001). Five variants were non-synonymous, including AOAH rs7986 (P=0.0017), ZAN rs539445 (P=0.00078) and rs542137 (P=0.00078), RAG1 rs3740955 (P=0.0014), and GBGT1 rs75765336 (P=0.0026). CONCLUSIONS: SNVs involved in mechanisms including DNA repair, inflammation, cellular adhesion, and cell signalling have significant associations with radiation response. SNVs with predictive power may stratify patient populations according to likelihood of responding to treatment, therefore enabling more efficient identification of beneficial strategies for pain management and improved resource utilisation.

Genetic biomarkers associated with changes in quality of life and pain following palliative radiotherapy in patients with bone metastases.

BACKGROUND: Patients with bone metastases undergoing palliative radiation therapy (RT) may experience changes in both the functional and symptomatic aspects of quality of life (QOL). The European Organization of Cancer Research and Treatment (EORTC) QOL Questionnaire Core-15 Palliative (QLQ-C15-PAL) is a validated questionnaire employed to assess QOL specifically in palliative patients. Our study aimed to identify single-nucleotide variant (SNV) genetic biomarkers associated with changes in QOL and pain. METHODS: Fifty-two patients who received a single 8-Gy RT for painful bone metastases completed the EORTC QOL-C15-PAL questionnaire prior to randomization and at 42-day post RT. Saliva samples obtained at day of RT were sequenced, and SNVs from genes involved in inflammation, radiation response, immune response, DNA damage, or QOL were assessed for association with changes in global QOL or the pain scale items using the Cochran-Armitage trend test. The penalized LASSO method with minimum Bayesian information criterion was used to select a multi-SNV model out of significant SNVs (P<0.005) and to produce prognostic scores for patients that categorized them into risk groups of low, middle, and high. RESULTS: The multivariable model predicting global QOL included 14 SNVs, of which HS1BP3 rs35579164 G:C and ABCA1 rs2230805 C>T had the largest positive and negative effect sizes, respectively (HS1BP3: 8.21, ABCA1: -3.44). The model for the response of QOL pain item included 8 SNVs, of which PLAUR rs4760 A>G and ELAC2rs11545302 had the largest positive and negative effect sizes, respectively (PLAUR: 5.23; ELAC: -3.84). The patients' risk groups were highly predictive of QOL response (P<0.0001) and pain item response (P<0.0001). In logistic regression analysis accounting for baseline factors of gender and primary cancer site, the global QOL risk group predicts pain response after RT [OR: 2.1, 95% confidence interval (CI): 1.2-3.9, P=0.015], but the QOL pain item risk group did not (OR: 0.93; 95% CI: 0.5-1.6, P=0.79). The multi-SNVs model included SNVs from genes involved in metabolism, membrane transport, cell cycle control, ciliary structure, and gene expression regulation. CONCLUSIONS: SNVs were significantly associated with changes in global QOL of global domain and pain item in patients with bone metastases. Identification of genetic biomarkers predictive of QOL items may allow patients and health care providers anticipate and better address the needs of the palliative cancer patient population.

Genetic biomarkers associated with pain flare and dexamethasone response following palliative radiotherapy in patients with painful bone metastases.

BACKGROUND: In patients who receive palliative radiation therapy (RT) for painful bone metastases, 40% experience a transient increase in pain known as a pain flare. Prophylactic dexamethasone has been shown to reduce pain flare incidence to 25%. We aimed to identify DNA biomarkers associated with pain flare and dexamethasone response. METHODS: Daily pain levels were recorded by 81 patients who received a single 8 Gy RT for painful bone metastases, of which 50 also received prophylactic dexamethasone. To identify single-nucleotide variants (SNVs), patient saliva samples obtained at day of RT were sequenced for 4,813 disease-associated genes, then filtered for genes associated with inflammation, radiation or immune response, and DNA damage. Significant SNVs (P<0.005) identified by the Cochran-Armitage trend test underwent the Penalized LASSO method with minimum Bayesian Information Criterion to select a multi-SNV model that jointly predicted pain flare, and pain flare despite prophylactic dexamethasone (dexamethasone response). The corresponding estimated effects of the multi-SNVs were used to drive the prognostic score of developing pain flare for each patient, who were divided into three risk groups of roughly equal sizes. RESULTS: Risk groups were significantly predictive of pain flare (P<0.0001) and dexamethasone response (P<0.0001). The high-risk patient groups had a 78% chance of developing pain flare, and pain flare despite dexamethasone [OR =24.6, 95% confidence interval (CI): 1.8-342.7, P=0.02]. The multivariable model for pain flare included 15 variants, with effect sizes ranging from -4.97 (NBPF1 rs3872309 C>T) to 5.54 (DNM2 10940838 A>C). The multivariable model for dexamethasone response included 6 variants, with effect sizes ranging from -1.03 (NBPF1 rs3872309 C>T) to 0.85 (TSEN54 rs62088470 C>G). CONCLUSIONS: Significant SNVs associated with pain flare were found in genes with functions in biosynthesis (DHODH, PECR), lipid excretion and metabolism (UGT2A1/2, VLDLR), and intracellular signalling (DNM2, SEC23A). Significant SNVs associated with dexamethasone response were from genes involved in extracellular matrix (HAS1, ADAMTS16) and cytoskeleton regulation (GAS2L2). Identification of SNVs predictive of pain flare and dexamethasone response enables targeted prophylactic therapy according to a patient's predisposed response.

Effect of Radiotherapy on Painful Bone Metastases: A Secondary Analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23.

IMPORTANCE: 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. OBJECTIVE: To investigate QOL at days 10 and 42 after radiotherapy with a bone metastases-specific QOL tool. DESIGN, SETTING, AND PARTICIPANTS: 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). INTERVENTIONS: Patients were treated with a single 8-Gy radiotherapy dose for 1 or 2 bone metastases. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01248585.

Classification of painful bone metastases as mild, moderate, or severe using both EORTC QLQ-C15-PAL and EORTC QLQ-BM22.

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.

Minimal clinically important differences in the EORTC QLQ-BM22 and EORTC QLQ-C15-PAL modules in patients with bone metastases undergoing palliative radiotherapy.

PURPOSE: Validated tools for evaluating quality of life (QOL) in patients with bone metastases 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 metastases 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 anchor-based 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. CLINICAL TRIALS REGISTRY: NCT01248585.

A prospective study validating the EORTC QLQ-BM22 bone metastases module in patients with painful bone metastases undergoing palliative radiotherapy.

PURPOSE: Quality of life (QOL) can be compromised in patients with bone metastases, and validated QOL instruments are required to accurately measure QOL outcomes in this population. This study investigated the validity, reliability and responsiveness of the EORTC QLQ-BM22 module with the EORTC QLQ-C15-PAL instrument in bone metastases. METHODS: The studied patients underwent palliative radiotherapy to bone metastases in the randomized NCIC CTG SC 23 trial. Multi-trait scaling analysis was performed to determine convergent and divergent validity among scales. Pearson coefficients were calculated to determine the correlation between items of the two instruments. The clinical validity and responsiveness of the QLQ-BM22 was tested by known group comparisons of different performance status and response to radiotherapy. RESULTS: 204 patients completed both questionnaires at baseline and 42day follow-up. On multi-trait scaling analysis, there was mixed evidence of construct validity (explained by the questionnaire format and population characteristics). There was little correlation between most QLQ-BM22 and QLQ-C15-PAL items (except for conceptually related scales) validating their complementary nature. There were statistically significant differences in all QLQ-BM22 scale scores in groups with KPS<80 vs. KPS⩾80 and three out of four QLQ-BM22 scale scores in "responders" vs. "non-responders" to radiotherapy. In patients who responded to radiotherapy, there were statistically significant differences in all QLQ-BM22 scale scores between baseline and follow-up. CONCLUSION: This study further validates the use of the QLQ-BM22 as a robust and sensitive instrument to assess QOL in patients with bone metastases treated with palliative radiotherapy.

Predictive model for survival in patients having repeat radiation treatment for painful bone metastases.

PURPOSE: To establish a survival prediction model in the setting of a randomized trial of re-irradiation for painful bone metastases. METHODS: Data were randomly divided into training and testing sets with an approximately 3:2 ratio. Baseline factors of gender, primary cancer site, KPS, worst-pain score and age were included with backward variable selection to derive a model using the training set. A partial score was assigned by dividing the value of each statistically significant regression coefficient by the smallest statistically significant regression coefficient. The survival prediction score (SPS) was obtained by adding together partial scores for the variables that were statistically significant. Three risk groups were modelled. RESULTS: The training set included 460 patients and the testing set 351 patients. Only KPS and primary cancer site reached the 5%-significance level. Summing up the partial scores assigned to KPS (90-100, 0; 70-80, 1; 50-60, 2) and primary cancer site (breast, 0; prostate, 1.3; other, 2.6; lung, 3) totalled the SPS. The 1/3 and 2/3 percentiles of the SPS were 2 and 3.6. For the testing set, the median survival of the 3 groups was not reached, 11.3 (95% C.I. 8.5 - not reached) and 5.2 months (95% C.I. 3.7-6.5). The 3, 6 and 12 month survival rates for the worst group were 64.4% (95% C.I. 55.3-72.1%), 43.0% (95% C.I. 34.0-51.8%) and 19.7% (95% C.I. 12.4-28.1%) respectively, similar to that in the training set. CONCLUSION: This survival prediction model will assist in choosing dose fractionation. We recommend a single 8 Gy in the worst group identified.

Revisiting classification of pain from bone metastases as mild, moderate, or severe based on correlation with function and quality of life.

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.

Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial.

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.

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.

Competing risks of death in younger and older postmenopausal breast cancer patients.

AIM: To show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death. METHODS: MA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models. RESULTS: The analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality. CONCLUSION: We demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Impact of reirradiation of painful osseous metastases on quality of life and function: a secondary analysis of the NCIC CTG SC.20 randomized trial.

PURPOSE: We previously demonstrated that 48% of patients with pain at sites of previously irradiated bone metastases benefit from reirradiation. It is unknown whether alleviating pain also improves patient perception of quality of life (QOL). PATIENTS AND METHODS: We used the database of a randomized trial comparing radiation treatment dose fractionation schedules to evaluate whether response, determined using the International Consensus Endpoint (ICE) and Brief Pain Inventory pain score (BPI-PS), is associated with patient perception of benefit, as measured using the European Organisation for Resesarch and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and functional interference scale of the BPI (BPI-FI). Evaluable patients completed baseline and 2-month follow-up assessments. RESULTS: Among 850 randomly assigned patients, 528 were evaluable for response using the ICE and 605 using the BPI-PS. Using the ICE, 253 patients experienced a response and 275 did not. Responding patients had superior scores on all items of the BPI-FI (ie, general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life) and improved QOL, as determined by scores on the EORTC QLQ-C30 scales of physical, role, emotional and social functioning, global QOL, fatigue, pain, and appetite. Similar results were obtained using the BPI-PS; observed improvements were typically of lesser magnitude. CONCLUSION: Patients responding to reirradiation of painful bone metastases experience superior QOL scores and less functional interference associated with pain. Patients should be offered re-treatment for painful bone metastases in the hope of reducing pain severity as well as improving QOL and pain interference.

Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial.

INTRODUCTION: Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis. METHODS: We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/- octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14). RESULTS: Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels. CONCLUSIONS: The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study. TRIAL REGISTRATION: NCT00002864, http://clinicaltrials.gov/show/NCT00002864.

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.