Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

The Role of Denosumab for Surgical Outcomes in Patients with Giant Cell Tumour of Bone: A Systematic Review.

Background: The role of denosumab in patients with resectable giant cell tumour of bone remains unclear. We asked the following research question: for patients (aged ≥ 12 years) with resectable giant cell tumour of bone, what are the benefits and harms of denosumab compared with no denosumab in terms of (1) facilitation of surgery (operative time, blood loss), (2) disease recurrence, (3) pain control, (4) disease stability, and (5) adverse effects (e.g., malignant transformation, osteonecrosis of jaw, atypical femur fracture)? One previous systematic review addressed only one outcome-disease recurrence. Therefore, we undertook this new systematic review to address the above five outcomes. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases were searched on June 30, 2020. Results: This systematic review included one previous systematic review and five comparative studies. Due to poor quality, non-randomized studies fraught with selection bias, it is difficult to determine if a significant difference exists in the outcomes for surgical giant cell tumour of bone with perioperative denosumab. There were no reported cases of adverse effects from denosumab. Conclusion: To date, there is insufficient evidence to understand the value of denosumab in the perioperative setting in patients with giant cell tumour of bone.

Neurocognitive outcomes following fetal exposure to chemotherapy for gestational breast cancer: A Canadian multi-center cohort study.

BACKGROUND: Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). The purpose of this study was to compare long-term neurocognitive, behavioral, developmental, growth, and health outcomes of children exposed in-utero to chemotherapy for BC. METHODS: This is a multi-center matched cross-sectional cohort study involving seven cancer centers across the region of Southern Ontario (Canada), and the Hospital for Sick Children (Toronto, Ontario). Using standardized psychological and behavioral tests, we compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to age-matched pairs exposed to known non-teratogens. RESULTS: We recruited 17 parent-child pairs and their matched controls. There were more preterm deliveries in the chemotherapy-exposed group compared to controls (p < 0.05). Full Scale IQ of children in the chemotherapy group was significantly confounded by maternal IQ and prematurity. Exposed children born at term were not different in cognitive outcomes. Children from both groups were similar in their developmental milestones, pediatric anthropometric measurements and health problems. There were no cases of autoimmune cytopenia. CONCLUSIONS: This is the first Canadian prospective comparative study designed to assess pediatric cognition following prenatal exposure to chemotherapy for BC. Chemotherapy was not found to be neurotoxic in this cohort and did not affect pediatric health. The decision to plan a preterm birth for initiating or continuing chemotherapy treatment must be taken into consideration in context of pediatric implications. While these results may assist in such decision making, replication with a larger sample is needed for more conclusive findings.

Feasibility and Effectiveness of Implementing a Novel Exercise and Self-Management Programme during Chemotherapy for Women with Breast Cancer: A Pilot Randomized Controlled Trial.

Purpose: The aim of this study was to determine the feasibility and effectiveness of implementing a novel exercise and self-management programme for women with breast cancer during chemotherapy. Method: The study used a pilot implementation design with a randomized controlled trial methodology. The 26 participants were adult breast cancer survivors (Stages 1-3) undergoing chemotherapy treatment. The intervention group received eight sessions of individualized, supervised, moderate-intensity aerobic exercise, paired with self-management modules in the cancer institution; the comparison group received usual care. The primary outcome assessed was feasibility of the implementation strategies. The secondary outcomes - level of physical activity, quality of life, exercise knowledge and behaviour, and perception of health status - were assessed at baseline, post-intervention, and 2- and 4-month follow-up. Descriptive statistics were used to measure the feasibility outcomes (recruitment rate, retention rate, adherence rate, and number of adverse events). A repeated-measures analysis of covariance was used to compare the secondary outcomes between the intervention and control groups at various time points. Results: The recruitment rate was 96%, retention rate was 100%, and adherence rate was 89%. No adverse events occurred. A between-groups difference was found for levels of physical activity post-intervention (mean difference = 25.38 points on the Godin Leisure-Time Exercise Questionnaire; 95% CI: 9.34, 41.42). There were no other significant findings. Conclusions: The implementation strategy was feasible. This programme has the potential to improve women's physical activity level during chemotherapy. Further research is needed to determine strategies to help survivors maintain these results over the long term.

Objectif : déterminer la faisabilité et l'efficacité de mettre en œuvre un nouveau programme d'exercices et d'autogestion pour les femmes atteintes d'un cancer du sein pendant la chimiothérapie. Méthodologie : essai pilote aléatoire et contrôlé auprès de 26 adultes survivantes du cancer du sein (de stades 1 à 3) sous chimiothérapie. Le groupe d'intervention a suivi huit séances d'exercice aérobique personnalisées et supervisées d'intensité modérée, associées à des modules d'autogestion donnés à l'établissement d'oncologie, et le groupe témoin a reçu les soins habituels. Le résultat primaire était la faisabilité des stratégies de mise en œuvre. Les chercheurs ont évalué les résultats secondaires (niveau d'activité physique, qualité de vie, connaissance des exercices et comportement face aux exercices et perception de l'état de santé) au début, après l'intervention et au suivi au bout de deux et quatre mois. Ils ont utilisé des statistiques descriptives pour mesurer les résultats de faisabilité (taux de recrutement, taux de rétention, taux d'adhésion et nombre d'événements indésirables) et utilisé des mesures de covariance répétées pour comparer les résultats secondaires entre le groupe d'intervention et le groupe témoin à divers moments. Résultats : le taux de recrutement s'est élevé à 96 %, le taux de rétention à 100 %, et le taux d'adhésion à 89 %. Aucun événement indésirable ne s'est produit. Les chercheurs ont constaté une différence entre les groupes à l'égard du niveau d'activité physique après l'intervention (différence moyenne de 25,38 points sur l'échelle de Godin [IC à 95 % : 9,34; 41,42]). Ils n'ont fait aucune autre observation significative. Conclusion : la stratégie de mise en œuvre était faisable. Ce programme a le potentiel d'améliorer le niveau d'activité physique de la femme pendant la chimiothérapie. Il faudra réaliser des recherches plus approfondies pour déterminer les stratégies nécessaires qui aideront les survivants à maintenir ces résultats à long terme.

Bridging the gap: incorporating exercise evidence into clinical practice in breast cancer care.

PURPOSE: To determine the feasibility (recruitment, retention, and adherence rates) of implementing a multi-dimensional knowledge translation (KT) intervention designed for women with breast cancer, and to explore preliminary estimates of effects of the implementation strategy on exercise level, exercise knowledge and behavior, health-related quality of life, and overall health status among breast cancer survivors. METHODS: Design: Implementation Trial. PARTICIPANTS: Community-dwelling women, over 18 years of age, currently undergoing chemotherapy for stage 1-3 BRCA. Randomization and Blinding: A blinded researcher randomized participants on a record-by-record basis to the intervention or control group. A researcher blinded to the group allocation of the participants conducted the statistical analysis. Intervention Group: Eight sessions of moderate intensity aerobic exercise along with eight self-management modules were delivered during chemotherapy within the cancer institution. CONTROL GROUP: Usual care. PRIMARY OUTCOME: Feasibility of implementation strategy measured through recruitment, retention, and adherence rates. RESULTS: Twenty-nine women were screened for this study. Twenty-seven met inclusion criteria and twenty-six participants were enrolled in the study. The implementation strategy was determined to be feasible and had a recruitment rate of 96%, retention rate of 100%, and adherence rate of 89%. The intervention group had significantly higher exercise levels (mean difference = 25.38, 95%CI = (9.35, 41.42)) post-intervention compared with the control group. No adverse events were reported. CONCLUSIONS: The implementation of this KT intervention is feasible and demonstrates preliminary effects for secondary outcomes for women with breast cancer during chemotherapy. Findings support the implementation of this intervention in a multi-center trial. TRIAL REGISTRATION: NCT03087461.

Interventions for reducing unplanned paediatric admissions: an observational study in one hospital.

OBJECTIVE: Evidence on how best to intervene to improve paediatric acute care and therefore reduce unplanned hospital admissions is weak. We describe service evaluation work at one hospital to assess interventions at critical clinical and service decision points. DESIGN: We conducted an observational study using routine daily-collected data (April 2009-December 2015) from a medium-sized district general hospital in south-west UK, using before-and-after comparisons of admissions-related data to evaluate two interventions implemented in April and November 2014, respectively: (1) an advice and guidance (A&G) phone line, where a senior paediatrician is available for general practitioners (GPs) and emergency department (ED) and (2) a Short Stay Paediatric Assessment Unit (SSPAU). We analysed data on all admitted children (<18 years) in the catchment area (population estimate 27 740 in 2015). Outcomes were GP-referred attendances, ward admissions, less than 1 day admissions and length of stay. RESULTS: A&G phone line was associated with a reduction in the mean number of less than 1 day admissions per month (difference in means before and after intervention -16.6 (95% CI -0.2 to -32.9)) and an increase in overall monthly bed-days (difference 72.5 (95% CI 21.0 to 124.0)), but there was little evidence of a change in GP-referred attendances or ward admissions. SSPAU was associated with a reduction in the mean number of monthly ward admissions (difference -34.6 (95% CI -21.3 to -48.0)) and less than 1 day admissions (difference in means -21.7 (95% CI -8.4 to -35.1)) and a reduction in the mean number of overall bed-days per month (difference -50.2 (95% CI -12.1 to -88.3)). CONCLUSIONS: Interventions for reducing time taken to senior clinician review may be effective in better managing paediatric acute care. Further work should explore results by age, condition and injury/illness status.

Physical Activity and Breast Cancer: A Qualitative Study on the Barriers to and Facilitators of Exercise Promotion from the Perspective of Health Care Professionals.

Purpose: We determined the barriers to and facilitators of exercise promotion by health care professionals (HCPs) for women with breast cancer (BC). Methods: The study was a qualitative descriptive study. Semi-structured interviews were conducted with HCPs who treat individuals with BC in Ontario. The interviews were recorded and transcribed. Two reviewers independently used content analysis to determine codes and themes developed in the interviews. NVivo 10 was used during the coding process. Results: A total of 24 HCPs participated in this study. The data from the interviews were grouped into five main categories: (1) institutional barriers, (2) HCP barriers, (3) perceived patient barriers, (4) facilitators (resource and service needs), and (5) patient characteristics. A graphic depiction of the interaction was created for these categories and how they affect the promotion of exercise for women with BC. Conclusions: Participants in this study identified several barriers to exercise promotion at the institutional, professional, and patient levels and suggested several strategies to facilitate exercise promotion. These findings can inform future exercise interventions to increase exercise adherence and engagement in this population.

Objectif : déterminer les obstacles et les facteurs facilitants de la promotion de l'exercice par les professionnels de la santé (PS) auprès de femmes atteintes du cancer du sein (CS). Méthodes : il s'agit d'une étude qualitative descriptive. Des entrevues semi-structurées ont été menées avec les participants. Les entrevues ont été enregistrées et transcrites. Deux examinateurs ont analysé indépendamment le contenu pour déterminer les codes et les thèmes abordés durant les entrevues. NVivo 10 a été utilisé durant le processus de codage. Résultats : au total, 24 PS ont participé à cette étude. Les données des entrevues ont été groupées en cinq catégories principales : (1) obstacles organisationnels, (2) obstacles liés aux PS, (3) obstacles perçus des patientes, (4) facteurs facilitants : ressources et services requis et (5) caractéristiques des patients. Une représentation graphique de l'interaction de ces catégories et de la manière dont elles influencent la promotion de l'exercice chez les femmes atteintes de CS a été créée. Conclusions : les participants à l'étude ont ciblé certains obstacles à la promotion de l'exercice liés à l'organisation, aux professionnels et aux patientes et ont suggéré certaines stratégies pour faciliter la promotion de l'exercice. Ces résultats peuvent guider les interventions liées à l'exercice afin d'augmenter l'adhésion et l'engagement de cette population.

A Translational Study of the Neoplastic Cells of Giant Cell Tumor of Bone Following Neoadjuvant Denosumab.

BACKGROUND: Giant cell tumor of bone is a primary bone tumor that is treated surgically and is associated with high morbidity in many cases. This tumor consists of giant cells expressing RANK (receptor activator of nuclear factor-κB) and mesenchymal spindle-like stromal cells expressing RANKL (RANK ligand); the interaction of these cells leads to bone resorption. Denosumab is a monoclonal antibody that binds RANKL and directly inhibits osteoclastogenesis. Clinical studies have suggested clinical and histological improvement when denosumab was administered to patients with a giant cell tumor. However, no studies have yet examined the viability and functional characteristics of tumor cells following denosumab treatment. METHODS: Specimens were obtained from six patients with a histologically confirmed giant cell tumor. Two of the patients had been treated with denosumab for six months. Primary cultures of stromal cells from fresh tumor tissue were established. Cell proliferation was measured over a two-day time course. The expression of RANKL and osteoprotegerin was analyzed with use of real-time PCR (polymerase chain reaction). RESULTS: Histological specimens from both patients who had completed denosumab treatment showed the absence of giant cells but persistence of stromal cells. Cell proliferation studies indicated that proliferation of stromal cells cultured from clinical specimens following denosumab treatment was approximately 50% slower than that of specimens from untreated patients. The expression of RANKL in the specimens from the treated patients was almost completely eliminated. CONCLUSIONS: Once the giant cell tumor tissue was no longer exposed to denosumab, the stromal cells continued to proliferate in vitro, albeit to a lesser degree. However, they also showed almost complete loss of RANKL expression. CLINICAL RELEVANCE: It is clear that treatment with denosumab only partially addresses the therapeutic need of patients with a giant cell tumor by wiping out the osteoclasts but leaving the neoplastic stromal cells proliferative.

Oncologists' strategies and barriers to effective communication about the end of life.

PURPOSE: Communicating about the end of life with patients has been reported as one of the most difficult and stressful part of the work of oncologists. Despite this fact, oncologists receive little training in this area, and many do not communicate effectively with patients. The purpose of this analysis, part of a larger study examining oncologists' experiences of patient loss, was to explore oncologists' communication strategies and communication barriers when discussing end-of-life issues with patients. METHODS: Twenty oncologists were interviewed at three hospitals about their communication strategies on end-of-life issues with patients. The data were analyzed using the grounded theory method. RESULTS: The findings revealed the strategies to effective communication about the end of life included: being open and honest; having ongoing, early conversations; communicating about modifying treatment goals; and balancing hope and reality. Barriers to implementing these strategies fell broadly into three domains, including physician factors, patient factors, and institutional factors. Physician factors included difficulty with treatment and palliation, personal discomfort with death and dying, diffusion of responsibility among colleagues, using the "death-defying mode," lack of experience, and lack of mentorship. Patient factors included, patients and/or families being reluctant to talk about the end of life, language barriers, and younger age. Institutional factors included stigma around palliative care, lack of protocol about end-of-life issues; and lack of training for oncologists on how to talk with patients about end-of-life issues. CONCLUSION: We conclude by drawing implications from our study and suggest that further research and intervention are necessary to aid oncologists in achieving effective communication about end-of-life issues.

Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial.

PURPOSE: In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS: We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS: In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION: This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Oncologists' protocol and coping strategies in dealing with patient loss.

To identify what protocol and coping strategies oncologists turn to cope with patient loss, the authors interviewed 20 oncologists at 3 hospitals. Using the grounded theory method, findings revealed that their protocol may include meeting with families, participating in bereavement rituals, making a phone call, or sending a condolence card. Coping strategies included social support, activity-oriented coping, turning to faith, compartmentalization, and withdrawing from patients and families. The authors conclude by offering implications from this research on how to address oncologists' grief over patient loss in institutional settings in order to improve bereavement care for families and enhance oncologists' quality of life.

Difficult patient loss and physician culture for oncologists grieving patient loss.

BACKGROUND: While caring for critically ill and terminal patients can elicit grief symptoms in health care professionals, few studies have examined oncologists' grief over patient loss using a qualitative approach to inquiry. OBJECTIVES: To explore what makes patient loss difficult for oncologists and to explore the context in which these losses were occurring. METHOD: Twenty oncologists were interviewed at three oncology centers in Canada about their experiences of grief over patient loss. Exclusion criteria included never having lost a patient in their care and being unable to speak English. Data was analyzed using the grounded theory method. RESULTS: Oncologists found patient loss particularly difficult for relational reasons including instances where they felt close to patients and their families, when they had a transference to the patient, when patients died young, when they had long-term patients, and when deaths were unexpected. Contextual reasons included when patients and their families were unprepared for death, had unrealistic expectations about cure, when excessive treatments were perceived to be used, when physicians were blamed for the loss, or when families were chaotic or had high needs. Findings further revealed that these losses were occurring within a physician culture that had a stigma around death and dying, viewed emotion as weakness, was focused on cure, and was gendered. CONCLUSIONS: Effective interventions to help oncologists cope with grief must identify the expectation gaps between physicians and patients when it comes to end-of-life care.

Interleukin-21 has activity in patients with metastatic melanoma: a phase II study.

PURPOSE: We report a multicenter phase II study of patients with metastatic melanoma (MM), evaluating the efficacy, toxicity, progression-free survival (PFS), immunogenicity, and biomarker profile of interleukin-21 (IL-21). PATIENTS AND METHODS: Patients with no prior systemic therapy and with limited-disease MM were treated with IL-21 by using three different dosing regimens. Cohort 1 received 50 µg/kg per day by outpatient intravenous bolus injection for 5 days of each week during weeks 1, 3, and 5 of an 8-week cycle. Cohort 2 received 30 µg/kg per day on the same schedule, and cohort 3 received 50 µg/kg per day for 5 days of each week during weeks 1 and 3 of a 6-week cycle. RESULTS: Forty patients were enrolled: three in cohort 1, 30 in cohort 2, and seven in cohort 3. Two patients in cohort 1 and four in cohort 3 had dose-limiting toxicities; all other patients were treated with a dose of 30 µg/kg per day. Common adverse events were fatigue, rash, diarrhea, nausea, and myalgia. Overall response rate (ORR) was 22.5%, with nine confirmed partial responses (median response duration, 5.3 months); 16 had stable disease (median response duration, 5.3 months). ORR did not appear to depended on IL-21 receptor expression or BRAF mutation status. The median PFS was 4.3 months and median overall survival (OS) was 12.4 months (95% CI, 10.09 to 17.81 months). CONCLUSION: The ORR to IL-21 is 22.5% for first-line MM and warrants further investigation. The favorable PFS and OS suggest that this is an active agent in comparison to both historical NCIC Clinical Trials Group data and data from meta-analysis of Cooperative Group phase II trials.

What do oncologists want? Suggestions from oncologists on how their institutions can support them in dealing with patient loss.

PURPOSE: The purpose of the study was to explore what institutional support(s) oncologists want to help them cope with patient loss. METHODS: The grounded theory method was used. Twenty oncologists were recruited and interviewed between November 2010 and July 2011 from three adult oncology centers in Ontario. Data collection and analysis took place concurrently. Analysis involved line-by-line coding, and was inductive, with codes and categories emerging from participants' narratives. RESULTS: Oncologists suggested institutional supports that fit under four categories that included: (1) training, information and education including fellowship training, grand rounds and the availability of fact sheets; (2) acknowledgment and validation of grief including normalizing grief, having forums to share experiences, supportive mentorship and group debriefing sessions; (3) institutional psychosocial support including access to professional help and the nursing care model; and (4) vacations and sabbaticals. CONCLUSIONS: Institutions such as medical schools and hospitals have both the opportunity and the obligation to support oncologists with this difficult aspect of their work. In addition to offering ongoing education and forums to share experiences, medical institutions can also provide supportive mentorship models to junior oncologists on how to cope with patient loss.

Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors.

PURPOSE: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS: Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

Reproducibility of peripheral quantitative computed tomography measurements at the radius and tibia in healthy pre- and postmenopausal women.

PURPOSE: The objectives of this study were to utilise the XCT-2000 pQCT scanner to determine the mean values and the reproducibility of in vivo total, trabecular, and cortical volumetric bone measurements at distal and diaphyseal sites of the radius and the tibia, as well as calf muscle and subcutaneous fat areas, in healthy pre- and postmenopausal women. METHODS: Twenty-nine women (14 premenopausal and 15 postmenopausal) were recruited to participate in this study. Distal and diaphyseal sites of the radius (at 4% and 20% of the length of the radius) and tibia (at 4%, 38%, and 66% of the length of the tibia) were examined. RESULTS: The root mean square coefficient of variation for measurements at the distal tibia gave the most favorable reproducibility values for total (1.5%) and trabecular (1.6%) density, whereas the diaphyseal tibia showed the most favorable reproducibility value for cortical density (0.3%). The root mean square coefficients of variation for measurements of muscle and fat cross-sectional areas at the calf were 0.6% and 0.7%, respectively. At the distal tibia, the mean values for total (P < .05) and trabecular (P < .01) density were significantly lower in postmenopausal women than in premenopausal women. CONCLUSIONS: The data presented here indicate that XCT-2000 pQCT scans at the tibia provide highly reproducible measurements of total, cortical, and trabecular bone as well as muscle and fat cross-sectional areas. Furthermore, significant differences in volumetric bone measurements between healthy pre- and postmenopausal women were evident only at the distal tibia, suggesting that this site warrants further study.

Primary tumor and patient characteristics in breast cancer as predictors of adjuvant therapy regimen: a regression model.

PURPOSE: Adjuvant therapy reduces the risk of recurrence of breast cancer. This study was undertaken to determine characteristics guiding choice of adjuvant therapy. METHODS: A retrospective review was completed of characteristics of patients with breast cancer (stages I-III) at a regional center from 2004 to 2007. Univariate analysis was used to select factors (P < 0.1) for entry into multivariate stepwise logistic regressions. Odds ratios with 95% confidence intervals were calculated. A P value of <0.05 was significant, and comparisons were two-tailed. RESULTS: Model 1 (n = 744) assessed the prescription of any adjuvant regimen (hormonal or chemotherapy). Indicators of choice of any regimen were positive lymph nodes [OR 16.5, CI (6.2, 44.0)], grade [4.0, (2.5, 6.0)], size [3.2, (2.1, 4.6)], PR [0.3, (0.1, 0.6)], and multicentricity [0.2 (0.04, 0.66)]. Model 2 (n = 663) assessed chemotherapy in ER+ patients. Indicators of addition of chemotherapy were stage [8.9 (4.3, 18.6), grade [5.5 (3.1, 9.6)], positive nodes [2.7 (1.1, 6.4)], physician experience [1.1 (1.0, 1.2)], age [0.8 (0.79, 0.86)], and year of treatment [0.8, (0.4, 0.9)]. Model 3 (n = 867) assessed prescription of a more aggressive chemotherapy regimen and indicators were treatment by a breast specialist oncologist [8.6 (1.7, 43.1)], stage [3.6 (2.4, 5.4)], positive nodes [2.6 (1.7, 4.1)], year of treatment [1.5 (1.3, 1.8)], size [1.2 (1.1, 1.4)], age [0.91 (0.89, 0.93)], and PR [0.4 (0.3, 0.6)]. CONCLUSIONS: This study verifies known factors for choice of adjuvant therapy, excludes others thought to be important, and quantifies effects at our center. Further studies are required to compare these models where risk stratification is different.

A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma.

BACKGROUND: The use of adjuvant chemotherapy to treat adults with localized resectable soft-tissue sarcoma remains controversial. The objective of this systematic review was to update the 1997 meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy of doxorubicin-based chemotherapy with respect to recurrence and survival. METHODS: A comprehensive literature search was performed to identify RCTs of adjuvant chemotherapy for adult patients diagnosed with localized resectable soft-tissue sarcoma. Two reviewers independently assessed eligibility and quality of the studies using a modified version of the Detsky Quality Scale. The outcome measures were local, distant, and overall recurrence and survival calculated through the fixed effect or random effect model. RESULTS: Four new eligible trials were identified allowing for a total of 18 trials representing 1953 patients to be included in the analysis. The odds ratios (OR) for local recurrence was 0.73 (95% confidence interval [CI] 0.56-0.94; P = .02) in favor of chemotherapy. For distant and overall recurrence the OR was 0.67 (95% CI 0.56-0.82; P = .0001) in favor of chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P = .09), which as not statistically significant. However, the OR for doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36-0.85; P = .01) in favor of chemotherapy. CONCLUSIONS: This updated meta-analysis confirms the marginal efficacy of chemotherapy in localized resectable soft-tissue sarcoma with respect to local recurrence, distant recurrence, overall recurrence, and overall survival. These benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens, but must be weighed against associated toxicities.

Cysteine-rich protein reverses weight loss in lung cancer patients receiving chemotherapy or radiotherapy.

Oxidative stress plays a role in the tumor-cytotoxic effect of cancer chemotherapy and radiotherapy and also in certain adverse events. In view of these conflicting aspects, a double-blind trial over a 6-month period was performed to determine whether a cysteine-rich protein (IMN1207) may have a positive or negative effect on the clinical outcome if compared with casein, a widely used protein supplement low in cysteine. Sixty-six patients with stage IIIB-IV non-small cell lung cancer were randomly assigned to IMN1207 or casein. Included were patients with a previous involuntary weight loss of > or =3%, Karnofsky status > or =70, and an estimated survival of >3 months. Thirty-five lung cancer patients remained on study at 6 weeks. Overall compliance was not different between treatment arms (42-44% or 13 g/day). The patients treated with the cysteine-rich protein had a mean increase of 2.5% body weight, whereas casein-treated patients lost 2.6% (p = 0.049). Differences in secondary endpoints included an increase in survival, hand-grip force, and quality of life. Adverse events were mild or moderate. Further studies will have to show whether the positive clinical effects can be confirmed and related to specific parameters of oxidative stress in the host.