Carolyn F. Wilson

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.

Randomized Trial of Tamoxifen Versus Combined Tamoxifen and Octreotide LAR Therapy in the Adjuvant Treatment of Early-Stage Breast Cancer in Postmenopausal Women: NCIC CTG MA.14

PURPOSE Somatostatin analogs act directly on breast cancer cells and indirectly on insulin and insulin-like growth factor 1 (IGF-1) levels. This trial was undertaken to assess whether octreotide would lower insulin and IGF-1 levels and reduce risk of breast cancer recurrence. PATIENTS AND METHODS The NCIC CTG MA.14 (NCIC Clinical Trials Group MA.14) trial randomly assigned postmenopausal women to 5 years of tamoxifen 20 mg daily (TAM) or TAM plus 2 years of octreotide 90 mg depot intramuscular injections monthly (TAM-OCT) as adjuvant therapy. The primary end point was event-free survival (EFS). Secondary end points were relapse-free survival (RFS), overall survival (OS), toxicity, and effects of treatment on IGF physiology. RESULTS Among 667 women with a median follow-up of 7.9 years, 220 events occurred-108 with TAM-OCT and 112 with TAM. Adjusted hazard ratios (HRs; TAM-OCT to TAM) were 0.93 for EFS (95% CI, 0.71 to 1.22; P = .62), 0.84 for RFS (95% CI, 0.59 to 1.18; P = .31), and 0.97 for OS (95% CI, 0.69 to 1.37; P = .86). Among patients with normal baseline gallbladder imaging, cholecystectomy was required in 23.0% of those receiving TAM-OCT but in only 1.4% of those receiving TAM (P < .001). At 4 months, TAM-OCT had significantly (P < .001) lowered IGF-1, IGF binding protein 3, and C-peptide levels. Older age (P = .02), tumor size (P = .001), nodal status (P = .01), high C-peptide levels (P < .001), and higher body mass index (BMI) in models excluding C-peptide (P < .001) were associated with poorer EFS in multivariate analysis. CONCLUSION Octreotide-related changes in circulating IGF-1 and C-peptide levels were statistically significant. Octreotide did not add significant clinical benefit. High C-peptide levels (surrogate for insulin secretion rate) and high BMI were associated with poor outcome.

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.

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 CTGs programmatic grant from the Canadian Cancer Society Research Institute.

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.

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

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.

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

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.

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.

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

PurposePrevious 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.MethodsWe 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).ResultsThe 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.ConclusionOur 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.