Publications by authors named "Abdenour Nabid"

43 Publications

The Clinical Significance of Bone Mineral Density Changes Following Long Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

J Urol 2021 Feb 12:101097JU0000000000001646. Epub 2021 Feb 12.

Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

Purpose: Long-term androgen deprivation therapy (LT-ADT) has been associated with decreased bone mineral density (BMD) in men with prostate cancer (PCa). Some evidence suggests that there is no impact on fracture risk despite this BMD loss. Our study aimed to quantify changes in BMD in men with high risk PCa on LT-ADT and calcium and vitamin D supplementation (CalVitD).

Materials And Methods: BMD analysis was conducted for localized high-risk prostate cancer patients enrolled in the phase III randomized trial PCS-V, comparing conventional and hypofractionated Radiation therapy (RT). Patients received 28 months of luteinizing hormone-releasing hormone agonist and CalVitD (500 mg of Calcium BID+400 IU of Vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of follow-up were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored.

Results: The lumbar spine, femoral neck and total femoral BMD were measured for 226, 231, and 173 patients, respectively. The mean percent change in BMD was -2.65%, -2.76% and -4.27%, for these respective sites (p <0.001 for all). The average decrease in BMD across all sites was -3.2%, with no decline in BMD category in most patients (83%). Eight-patients (4%) became osteoporotic.

Conclusions: Despite a mild decline in BMD, the change in clinical BMD category remained low with LT-ADT. Consequently, CalVitD alone may suffice for most localized PCa patients on LT-ADT.
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http://dx.doi.org/10.1097/JU.0000000000001646DOI Listing
February 2021

Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A randomised phase III trial.

Eur J Cancer 2021 Jan 3;143:64-74. Epub 2020 Dec 3.

McGill University Health Centre, CA, Canada.

Background: The role of androgen deprivation therapy (ADT) in combination with radiotherapy (RT) in intermediate-risk prostate cancer (IRPC) remains controversial, particularly in patients receiving dose-escalated RT (DERT). We compared outcomes between patients with IRPC treated with ADT and two different doses of RT vs. RT alone.

Methods: From December 2000 to September 2010, 600 patients with IRPC were randomised to a three-arm trial consisting of 6 months of ADT plus RT 70 Gy (ADT + RT70) vs. ADT plus a DERT of 76 Gy (ADT + DERT76) vs. DERT of 76 Gy alone (DERT76). Primary end-point was biochemical failure (BF), and secondary end-points were overall survival (OS) and toxicity. RT toxicity was assessed by Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria.

Findings: With a median follow-up of 11.3 years (interquartile range: 10.9-11.7), patients receiving DERT76 alone, compared with patients receiving ADT + RT70 and ADT + DERT76, had higher rates of BF (32%, 18% and 14%, respectively, p < 0.001), higher rates of prostate cancer progression (12%, 4.5% and 3.3%, respectively, p = 0.001) and more deaths due to prostate cancer (6.5%, 3.0% and 1.5%, respectively, p = 0.03) with no significant difference seen between ADT + RT70 and ADT + DERT76. There was no significant difference in OS between the 3 arms. A higher dose of RT (76 Gy) increased late gastrointestinal (GI) toxicity grade ≥ II compared with lower dose (70 Gy) (16% vs 5.3%, p < 0.001) with no statistical difference for late genitourinary toxicity.

Interpretation: In IRPC, the addition of 6 months of ADT to RT70 or DERT76 significantly improves BF and appears to decrease the risk of death from prostate cancer compared with DERT76 alone with no difference in OS. In the setting of IRPC, ADT plus RT 70 Gy yields effective disease control with a better GI toxicity profile. Clinicaltrials.gov#NCT00223145.
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http://dx.doi.org/10.1016/j.ejca.2020.10.023DOI Listing
January 2021

Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial.

Eur Urol 2018 10 3;74(4):432-441. Epub 2018 Jul 3.

McGill University Health Centre, Montréal, QC, Canada.

Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined.

Objective: The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT.

Design, Setting And Participants: From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT.

Outcome Measurements And Statistical Analysis: Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model.

Results And Limitations: With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88-95%) and 86% for short arm (83-90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of ≥10 points.

Conclusions: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC.

Patient Summary: In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life.
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http://dx.doi.org/10.1016/j.eururo.2018.06.018DOI Listing
October 2018

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

Qual Life Res 2018 Apr 29;27(4):1089-1098. Epub 2017 Nov 29.

Queen's University, Kingston, ON, Canada.

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.
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http://dx.doi.org/10.1007/s11136-017-1745-8DOI Listing
April 2018

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

Ann Palliat Med 2017 Dec 29;6(Suppl 2):S185-S194. Epub 2017 Aug 29.

Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.21037/apm.2017.08.12DOI Listing
December 2017

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.

Radiother Oncol 2018 Mar 5;126(3):541-546. Epub 2017 Nov 5.

Sunnybrook Odette Cancer Centre, University of Toronto, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.radonc.2017.10.006DOI Listing
March 2018

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.

Am J Hosp Palliat Care 2018 Apr 26;35(4):718-723. Epub 2017 Sep 26.

1 Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1177/1049909117733435DOI Listing
April 2018

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

JAMA Oncol 2017 Jul;3(7):953-959

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1001/jamaoncol.2016.6770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547919PMC
July 2017

Quality of life and swallowing with standard chemoradiotherapy versus accelerated radiotherapy and panitumumab in locoregionally advanced carcinoma of the head and neck: A phase III randomised trial from the Canadian Cancer Trials Group (HN.6).

Eur J Cancer 2017 02 29;72:192-199. Epub 2016 Dec 29.

Canadian Cancer Trials Group, Kingston, ON, Canada.

Aim: To compare quality of life (QOL) between standard (SFX) chemoradiotherapy (arm A) and altered fractionation radiotherapy (AFX) with panitumumab (PMab; arm B).

Methods: Patients with T any N + M0 or T3-4N0M0 squamous cell head-neck carcinoma were randomised to SFX (70 Gy/35/7 wks) plus cisplatin (100 mg/m IV × 3) versus AFX (70 Gy/35/6 wks) plus PMab (9 mg/kg IV × 3). QOL was collected at baseline, end of radiation therapy (RT) and 2, 4, 6, 12, 24 and 36 months post-RT using the Functional Assessment of Cancer Therapy Head and Neck (FACT-H&N), MD Anderson Dysphagia Index (MDADI) and SWAL-QOL. We hypothesised a 6-point more favourable change in FACT-H&N score from baseline to 1 year in arm B over arm A.

Results: Among 320 patients, median follow-up was 46 (range: 0.1-64.3) months, median age 56, 84% male, Eastern Cooperative Oncology Group PS 0 (71%), 1 (29%). Primary site was oropharynx in 81% (p16+ 68%, p16- 16%, missing 16%). Baseline scores did not differ by arm (A/B): FACT-H&N 116.5/115, MDADI Global 83/77, SWAL-QOL General 67/68. At 1 year, no difference was seen between arms in FACT-H&N change from baseline: A -1.70, B -4.81, p = 0.194. Subscale change scores by arm were (A/B): last week RT, FACT-Physical (-11.6, -10, p = 0.049), MDADI Physical (-40.4, -33.9, p = 0.045), and SWAL-QOL Eating Duration (-61.2, -51.2, p = 0.02), Eating Desire (-53.3, -43.9, p = 0.031) and Mental Health (-42, -32.6, p = 0.009); 4 months, HN subscale (-7.7, -10, p = 0.014). No clinically important differences by arm were seen post-treatment.

Conclusions: PMab with AFX did not durably improve QOL or swallowing as compared with SFX with cisplatin.

Trial Registration: ClinicalTrials.gov: NCT00820248.
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http://dx.doi.org/10.1016/j.ejca.2016.11.008DOI Listing
February 2017

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma: A Randomized Clinical Trial.

JAMA Oncol 2017 Feb;3(2):220-226

Canadian Cancer Trials Group, Kingston, Ontario, Canada.

Importance: The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).

Objective: To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab.

Design, Setting, And Participants: A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011.

Interventions: Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B).

Main Outcomes And Measures: Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety.

Results: Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25).

Conclusions And Relevance: With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies.

Trial Registration: clinicaltrials.gov Identifier: NCT00820248.
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http://dx.doi.org/10.1001/jamaoncol.2016.4510DOI Listing
February 2017

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

Support Care Cancer 2016 12 27;24(12):4871-4878. Epub 2016 Jul 27.

Queen's University, Kingston, ON, Canada.

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.
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http://dx.doi.org/10.1007/s00520-016-3341-9DOI Listing
December 2016

Acute and late urinary toxicity following radiation in men with an intact prostate gland or after a radical prostatectomy: A secondary analysis of RTOG 94-08 and 96-01.

Urol Oncol 2016 10 2;34(10):430.e1-7. Epub 2016 Jul 2.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address:

Introduction: To estimate the contribution of the prostate gland and prostatic urethral inflammation to urinary symptoms after radiation therapy for prostate cancer, we performed a secondary analysis of urinary toxicity after primary radiation to an intact prostate vs. postprostatectomy radiation to the prostatic fossa in protocols RTOG 94-08 and 96-01, respectively.

Materials And Methods: Patients randomized to the radiation-alone arms (without hormone therapy) of the 2 trials were evaluated, including 104 men receiving primary prostate radiation to 68.4Gy on RTOG 94-08 and 371 men receiving 64.8Gy to the prostatic fossa on RTOG 96-01. Acute and late urinary toxicity were scored prospectively by RTOG scales. Chi-square test/logistic regression and cumulative incidence approach/Fine-Gray regression model were used for analyses of acute and late toxicity, respectively.

Results: Grade≥2 acute urinary toxicity was significantly higher after primary prostatic radiation compared with postprostatectomy radiation (30.8% vs. 14.0%; P<0.001), but acute grade≥3 toxicity did not differ (3.8% vs. 2.7%; P = 0.54). After adjusting for age, primary radiation resulted in significantly higher grade≥2 acute urinary toxicity (odds ratio = 3.72; 95% CI: 1.65-8.37; P = 0.02). With median follow-up of 7.1 years, late urinary toxicity was not significantly different with primary vs. postprostatectomy radiation (5-year grade≥2: 16.7% vs. 18.3%; P = 0.65; grade≥3: 6.0% vs. 3.3%; P = 0.24).

Conclusions: Primary radiation to an intact prostate resulted in higher grade≥2 acute urinary toxicity than radiation to the prostatic fossa, with no difference in late urinary toxicity. Thus, a proportion of acute urinary toxicity in men with an intact prostate may be attributable to inflammation of the prostatic gland or urethra.
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http://dx.doi.org/10.1016/j.urolonc.2016.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035191PMC
October 2016

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

Radiother Oncol 2016 05 3;119(2):208-12. Epub 2016 May 3.

Queen's University, Kingston, Canada.

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.
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http://dx.doi.org/10.1016/j.radonc.2016.04.035DOI Listing
May 2016

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

Qual Life Res 2016 10 2;25(10):2535-2541. Epub 2016 May 2.

Queen's University, Kingston, ON, Canada.

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.
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http://dx.doi.org/10.1007/s11136-016-1308-4DOI Listing
October 2016

Prophylactic dexamethasone for radiation-induced bone-pain flare - Authors' reply.

Lancet Oncol 2016 Feb;17(2):e40-e41

Princess Margaret Hospital, Radiation Medicine Program, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1016/S1470-2045(16)00029-2DOI Listing
February 2016

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

Radiother Oncol 2016 Mar 26;118(3):547-51. Epub 2015 Oct 26.

Juravinski Hospital and Cancer Centre and McMaster University, Hamilton, Canada.

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.
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http://dx.doi.org/10.1016/j.radonc.2015.10.018DOI Listing
March 2016

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

Lancet Oncol 2015 Nov 18;16(15):1463-1472. Epub 2015 Oct 18.

Princess Margaret Hospital, Radiation Medicine Program, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1016/S1470-2045(15)00199-0DOI Listing
November 2015

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

Support Care Cancer 2016 Apr 23;24(4):1617-23. Epub 2015 Sep 23.

Juravinski Hospital and Cancer Centre and McMaster University, Hamilton, ON, Canada.

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.
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http://dx.doi.org/10.1007/s00520-015-2957-5DOI Listing
April 2016

Regional Nodal Irradiation in Early-Stage Breast Cancer.

N Engl J Med 2015 Jul;373(4):307-16

From the Department of Oncology, McMaster University, and Juravinski Cancer Centre, Hamilton, ON (T.J.W., M.N.L.), Tom Baker Cancer Centre, Calgary, AB (I.A.O., P.C.), BC Cancer Agency-Vancouver Island Centre, Victoria, BC (I.A.O.), Queen's University and NCIC Clinical Trials Group, Kingston, ON (W.R.P., Y.M., J.-A.W.C., B.E.C.), University of Toronto and Sunnybrook Odette Cancer Centre, Toronto (I.A., K.I.P.), Centre Universitaire de Sherbrooke at Fleurimont Hospital, Sherbrooke, QC (A.N.), Université de Montréal, Montreal (P.R.), Laval University and L'Hôtel-Dieu de Québec, Quebec, QC (A.F.), Princess Margaret Hospital, Toronto (L.M., D.R.M.), Cross Cancer Institute, Edmonton, AB (S.C.), Nova Scotia Cancer Centre, Halifax (M.C.N), Northeastern Ontario Regional Cancer Centre, Sudbury (J.B.), and BC Cancer Agency-Vancouver Centre, Vancouver, BC (K.G.) - all in Canada; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (B.H.C.); Cancer Research UK-Medical Research Council Oxford Institute for Radiation Oncology, Oxford, United Kingdom (K.A.V.); Ohio State University Wexner Medical Center, Columbus (J.R.W.); and the University of Michigan Comprehensive Cancer Center, Ann Arbor (L.J.P.).

Background: Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes.

Methods: We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival.

Results: Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001).

Conclusions: Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.).
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http://dx.doi.org/10.1056/NEJMoa1415340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556358PMC
July 2015

Effect of re-irradiation for painful bone metastases on urinary markers of osteoclast activity (NCIC CTG SC.20U).

Radiother Oncol 2015 Apr 14;115(1):141-8. Epub 2015 Mar 14.

Mount Vernon Hospital Cancer Centre, Northwood, UK.

Purpose: The NCIC CTG Symptom Control.20 randomized trial (SC.20) confirmed the effectiveness of re-irradiation to painful bone metastases. This companion study correlates urinary markers of osteoclast activity with response to re-irradiation, survival and skeletal related events (SREs).

Methods: Pain response was assessed using the International Consensus Endpoints. Urinary markers of bone turnover-pyridinoline (PYD), deoxypyridinoline (DPD), N-telopeptide (NTX), Alpha and Beta cross-laps of C-telopeptide (CTX)-before and 1month after re-irradiation were correlated to response to re-irradiation and then to both, either or none of the initial and re-irradiation: frequent responders (response to both); eventual responders (response to re-irradiation only); eventual non-responders (response to initial radiation only), and absolute non-responders (no response to both).

Results: Significant differences between 40 responders and 69 non-responders to re-irradiation existed for PYD (p=0.03) and DPD (p=0.04) at baseline. When patients were categorized as frequent responders (N=34), eventual responders (6), eventual non-responders (59) and absolute non-responders (10), the mean values of all markers in the absolute non-responders at baseline and the follow-up were about double those for the other three groups with statistically significant difference for DPD (p=0.03) at baseline. Absolute non-responders had the worst survival. The few occurrences of the SREs did not allow meaningful comparisons among the groups.

Conclusion: There were significant differences between responders and non-responders to re-irradiation for PYD and DPD at baseline. The urinary markers in the absolute non-responders were markedly elevated at both baseline and follow-up with a statistically significant difference for DPD at baseline.
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http://dx.doi.org/10.1016/j.radonc.2015.02.025DOI Listing
April 2015

Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck.

Int J Radiat Oncol Biol Phys 2015 Apr 7;91(5):907-15. Epub 2015 Feb 7.

Stanford University Medical Center, Stanford, California.

Purpose: This paper reports long-term results of RTOG 9903, to determine whether the addition of erythropoietin (EPO) would improve the outcomes of radiation therapy (RT) in mildly to moderately anemic patients with head and neck squamous cell carcinoma (HNSCCa).

Methods And Materials: The trial included HNSCCa patients treated with definitive RT. Patients with stage III or IV disease received concomitant chemoradiation therapy or accelerated fractionation. Pretreatment hemoglobin levels were required to be between 9.0 and 13.5 g/dL (12.5 g/dL for females). EPO, 40,000 U, was administered weekly starting 7 to 10 days before RT was initiated in the RT + EPO arm.

Results: A total of 141 of 148 enrolled patients were evaluable. The baseline median hemoglobin level was 12.1 g/dL. In the RT + EPO arm, the mean hemoglobin level at 4 weeks increased by 1.66 g/dL, whereas it decreased by 0.24 g/dL in the RT arm. With a median follow-up of 7.95 years (range: 1.66-10.08 years) for surviving patients and 3.33 years for all patients (range: 0.03-10.08 years), the 5-year estimate of local-regional failure was 46.2% versus 39.4% (P=.42), local-regional progression-free survival was 31.5% versus 37.6% (P=.20), and overall survival was 36.9% versus 38.2% (P=.54) for the RT + EPO and RT arms, respectively. Late toxicity was not different between the 2 arms.

Conclusions: This long-term analysis confirmed that despite the ability of EPO to raise hemoglobin levels in anemic patients with HNSCCa, it did not improve outcomes when added to RT. The possibility of a detrimental effect of EPO could not be ruled out.
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http://dx.doi.org/10.1016/j.ijrobp.2014.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657552PMC
April 2015

Effect of dutasteride in men receiving intermittent androgen ablation therapy: The AVIAS trial.

Can Urol Assoc J 2014 Nov;8(11-12):E789-94

Division of Urology, London Health Sciences Centre, London, ON.

Introducton: We studied the effect of dutasteride on the length of the off-treatment period in prostate cancer patients on intermittent androgen deprivation (IAD) therapy.

Methods: We conducted a randomized, placebo-controlled Phase II trial in men with localized prostate cancer and a rising prostate-specific antigen (PSA) level post-primary treatment. Patients were randomized to dutasteride (0.5 mg/day) or placebo. All patients received androgen deprivation therapy (ADT), which was stopped at month 9 if the PSA level was <1.0 ng/mL. ADT was resumed when PSA increased to ≥5.0 ng/mL. End points included time off treatment, PSA nadir after 9 months of ADT, serum testosterone and dihydrotestosterone levels, and time to castrate-resistant prostate cancer (rising PSA while testosterone levels remain <50 ng/mL).

Results: There were 87 evaluable patients: 49 dutasteride, 38 placebo. In total, 80 patients completed one treatment cycle: 45 dutasteride, 35 placebo. The median time off treatment for patients reaching ≥5 ng/mL was 18.6 and 16.7 months for dutasteride and placebo, respectively (p = 0.7600). The median PSA nadir at 9 months was 0.1 and 0.075 ng/mL, respectively (p = 0.4486). There were no cases of androgen-independent prostate cancer. Our study limitations include its short duration with only one treatment cycle evaluated.

Conclusions: This small-scale Phase II randomized controlled trial showed no benefit to the addition of dutasteride to an IAD regimen.
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http://dx.doi.org/10.5489/cuaj.2332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250242PMC
November 2014

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

J Clin Oncol 2014 Dec 27;32(34):3867-73. Epub 2014 Oct 27.

Edward Chow, Sunnybrook Odette Cancer Centre, University of Toronto; Rebecca K.S. Wong, Princess Margaret Hospital, Ontario Cancer Institute, University of Toronto, Toronto; Ralph M. Meyer, Juravinski Hospital and Cancer Centre and McMaster University, Hamilton; Bingshu E. Chen, Carolyn F. Wilson, and Michael Brundage, Cancer Research Institute, Queen's University, Kingston, Ontario; Jackson S.Y. Wu, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta; Abdenour Nabid, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada; Yvette M. van der Linden, Leiden University Medical Centre, Leiden and Radiotherapy Institute Friesland, Leeuwarden; Caroline J.A. Tissing-Tan, Institute for Radiation Oncology Arnhem, Arnhem; Bing Oei, Dr Bernard Verbeeten Instituut, Tilburg, the Netherlands; Daniel Roos, Royal Adelaide Hospital, University of Adelaide, Adelaide, South Australia, Australia; William F. Hartsell, Central DuPage Hospital Cancer Center, Warrenville, IL; Peter Hoskin, Mount Vernon Hospital Cancer Centre, Middlesex, United Kingdom; Scott Babington, Christchurch Hospital, Christchurch, New Zealand; and William F. Demas, Akron City Hospital, Northeast Ohio Medical University, Akron, OH.

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.
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http://dx.doi.org/10.1200/JCO.2014.57.6264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239305PMC
December 2014

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

Lancet Oncol 2014 Feb 23;15(2):164-71. Epub 2013 Dec 23.

Princess Margaret Hospital, Radiation Medicine Program, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1016/S1470-2045(13)70556-4DOI Listing
February 2014

Intermittent androgen suppression for rising PSA level after radiotherapy.

N Engl J Med 2012 Sep;367(10):895-903

British Columbia Cancer Agency, Cancer Centre for the Southern Interior, 399 Royal Ave., Kelowna, BC V1Y 5L3, Canada.

Background: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial.

Methods: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals.

Results: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24).

Conclusions: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).
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http://dx.doi.org/10.1056/NEJMoa1201546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521033PMC
September 2012

Safety and feasibility of motexafin gadolinium administration with whole brain radiation therapy and stereotactic radiosurgery boost in the treatment of ≤ 6 brain metastases: a multi-institutional phase II trial.

J Neurooncol 2011 Nov 27;105(2):301-8. Epub 2011 Apr 27.

Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, K4/B100, Madison, WI 53792, USA.

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.
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http://dx.doi.org/10.1007/s11060-011-0590-9DOI Listing
November 2011

Factors associated with weight loss during radiotherapy in patients with stage I or II head and neck cancer.

Support Care Cancer 2012 Mar 20;20(3):591-9. Epub 2011 Mar 20.

Department of Public Health, Saint-Etienne University Hospital, Cancer Institute of Loire, 108 bis avenue Albert Raimond, 42270 Saint Priest en Jarez, France.

Background: The purpose of the study was to identify factors associated with weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer.

Methods: This study was conducted as part of a phase III chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Patients' characteristics, dietary intake, health-related quality of life (HRQOL), tumor characteristic, treatment characteristics, and acute adverse effects of RT were evaluated at baseline and during RT. Factors independently associated with weight loss during RT were identified using the multiple linear regression (P ≤ 0.05).

Results: The mean weight loss during RT was 2.2 kg (standard deviation, 3.4). In bivariate analyses, the occurrence of adverse effects of RT and most of the HRQOL dimensions evaluated during RT were correlated with weight loss. In the multivariate analysis, eight factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P < 0.001), TNM stage II disease (P = 0.01), higher pre-RT body weight (P < 0.001), dysphagia before RT (P < 0.005), higher mucosa adverse effect of RT (P = 0.03), lower dietary energy intake during RT (P < 0.001), lower score of the digestive dimension on the Head and Neck Radiotherapy Questionnaire (P < 0.001) and a higher score of the constipation symptom on the EORTC QLQ-C30 during RT (P = 0.02).

Conclusions: The results underline the importance of maintaining energy intake in early stage HN cancer patients during RT and the importance of preventing and treating adverse effects.
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http://dx.doi.org/10.1007/s00520-011-1132-xDOI Listing
March 2012

Predictors of weight loss during radiotherapy in patients with stage I or II head and neck cancer.

Cancer 2010 May;116(9):2275-83

Clinical Epidemiology Unit, Laval University Cancer Research Center, CHUQ-Hôtel Dieu de Québec, Quebec City, Quebec, Canada.

Background: The purpose of the study was to identify predictors of weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer.

Methods: This study was conducted as part of a phase 3 chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Their baseline characteristics, including lifestyle habits, diet, and quality of life, were assessed as potential predictors. Predictors were identified using multiple linear regressions. The reliability of the model was assessed by bootstrap resampling. A receiver operating characteristics curve was generated to estimate the model's accuracy in predicting critical weight loss (>or=5%).

Results: The mean weight loss was 2.2 kg (standard deviation, 3.4). Five factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P<.001), higher pre-RT body weight (P<.001), stage II disease (P = .002), dysphagia and/or odynophagia before RT (P = .001), and a lower Karnofsky performance score (P = .028). There was no association with pre-RT lifestyle habits, diet, or quality of life. The bootstrapping method confirmed the reliability of this predictive model. The area under the curve was 71.3% (95% confidence interval, 65.8-76.9), which represents an acceptable ability of the model to predict critical weight loss.

Conclusions: These results could be useful to clinicians for screening patients with early stage HN cancer treated by RT who require special nutritional attention.
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http://dx.doi.org/10.1002/cncr.25041DOI Listing
May 2010

Health-related quality of life as a survival predictor for patients with localized head and neck cancer treated with radiation therapy.

J Clin Oncol 2009 Jun 18;27(18):2970-6. Epub 2009 May 18.

Laval University Cancer Research Center, CHUQ-HDQ, Québec, Canada.

Purpose: To assess the added prognostic value for overall survival (OS) of baseline health-related quality of life (HRQOL) and of early changes in HRQOL among patients with localized head and neck cancer (HNC) treated with radiation therapy.

Patients And Methods: All 540 patients with HNC who participated in a randomized trial completed two HRQOL instruments before radiation therapy: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Head and Neck Radiotherapy Questionnaire. Six months after the end of radiation therapy, 497 trial participants again completed the two HRQOL instruments. During the follow-up, 179 deaths were observed. Multivariate Cox proportional hazards models were used to test whether HRQOL variables, baseline and change, provided additional prognostic value beyond recognized prognostic factors.

Results: The baseline EORTC QLQ-C30 physical functioning (PF) score was an independent predictor of OS. The hazard ratio (HR) associated with a 10-point increment in baseline PF was 0.87 (95% CI, 0.81 to 0.94). In multivariate models, the change in HRQOL was significantly associated with OS for most HRQOL dimensions. Among these, PF change was the strongest predictor. The magnitude of the association between PF change and survival decreased over time. At 1 year, the HR associated with a positive PF change of 10 points was 0.75 (95% CI, 0.68 to 0.83). After PF is taken into account, no other HRQOL variable was associated with survival.

Conclusion: Our findings indicate that both baseline PF and PF change provide added prognostic value for OS beyond established predictors in patients with HNC. Assessing HRQOL could help better predict survival of cancer patients.
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http://dx.doi.org/10.1200/JCO.2008.20.0295DOI Listing
June 2009