Iryna Kuchuk

Incidence, consequences and treatment of bone metastases in breast cancer patients-Experience from a single cancer centre.

Background There is a paucity of literature about the benefits of bone-targeted agents for breast cancer patients with bone metastases treated in the non-trial setting. We explored the incidence, consequences, and treatment of bone metastases at a single cancer centre. Methods Electronic records of metastatic breast cancer patients were reviewed and pertinent information was extracted. Results Of 264 metastatic breast cancer patients, 195 (73%) developed bone metastases. Of these patients, 176 were eligible for analysis. Median age at bone metastases diagnosis was 56.9 years (IQR 48–67) and initial presentation of bone metastases included asymptomatic radiological findings (58%), bone pain (40%), or a SRE (12.5%). Most patients (88%) received a bone-targeted agent, starting a median of 1.5 months (IQR 0.8–3.30) after bone metastasis diagnosis. 62% of patients had ≥1 SRE. The median time from bone metastasis diagnosis to first SRE was 1.8 months (IQR 0.20–8.43 months). Median number of SREs per patient was 1.5 (IQR 0–3). Overall, 26.8% of all SREs were clinically asymptomatic. Within the entire cohort, 51% required opioids and 20% were hospitalized due to either an SRE or bone pain. Conclusions Despite extensive use of bone-targeted agents, the incidence of SREs remains high. Nearly half of SREs occur prior to starting a bone-targeted agent. Use of opioids and hospitalizations secondary to bone metastases remain common. More effective treatment options are clearly needed.

Incidence and consequences of bone metastases in lung cancer patients.

Background Bone metastases (BM) are common in NSCLC patients. Despite some potential positive effects of bone-targeted therapies, their use in NSCLC is infrequent, which may relate to the overall poor prognosis of advanced lung cancer. We reviewed the literature to evaluate the incidence, consequences and use of bone-targeting agents in lung cancer patients with BM in both the trial and non-trial clinical setting. Methods Published prospective and retrospective papers investigating lung cancer and BM, in trial and non-trial settings, were identified and are discussed in this review. Results BM are common in patients with advanced lung cancer and often present symptomatically with pain and skeletal related events (SREs). Patients with high bone turnover marker levels, multiple BM, and history of pathological fractures have shorter overall survival. In randomized studies bone-targeted therapies reduced the risk of SREs and prolonged the time to first SRE. The use of bone-targeted agents may also be associated with a survival benefit. Conclusion BM are a common problem in advanced lung cancer. While the benefits of bone-targeted therapies have been demonstrated, their use is limited in non-trial populations. If better predictive markers of individual risk were available this might increase the appropriate use of bone-targeted agents.

Use of Conjoint Analysis to Assess Breast Cancer Patient Preferences for Chemotherapy Side Effects

OBJECTIVE Our objective was to evaluate preferences associated with grade I/II and grade III/IV chemotherapy side effects among breast cancer patients receiving chemotherapy. We also assessed trade-offs that patients are willing to make between treatment side effects and the route and schedule of treatment administration. METHODS In this cross-sectional study, patients receiving chemotherapy for breast cancer completed a one-time Web survey. Conjoint analysis was used to elicit preferences for 17 grade I/II and III/IV side effects associated with available chemotherapies and regimens. In the analysis, the risk of each side effect was increased by 5%, holding all others constant, and the respective impact on patient preferences was identified. RESULTS A total of 102 women participated (mean age 54 ± 11). Among the grade I/II side effects, a 5% reduction in the risk of sensory neuropathy, nausea, and motor neuropathy had the highest impact on preferences. Among grade III/IV side effects, motor neuropathy, nausea/vomiting, and myalgia made the most difference. An oral twice-daily regimen was most preferred; however, patients were willing to receive an intravenous regimen relative to oral to avoid an increased risk of 5% in the majority of side effects. Avoiding an increased chance of grade III/IV motor neuropathy was associated with willingness to tolerate one of the least preferred administration schedules. CONCLUSION This study identified relative preferences among both mild/moderate to severe side effects from the patient perspective. Patients appear to be willing to make trade-offs between side effects and different regimens. These findings may help to inform medical decision-making processes.

The incidence and clinical impact of bone metastases in non-small cell lung cancer

INTRODUCTION Non-small cell lung cancer (NSCLC) is the leading global cause of cancer death. While bone metastases (BM) commonly cause morbidity, bone-targeted agent (BTA) use is variable. We investigated the incidence and impact of BM among unselected NSCLC patients. METHODS A retrospective chart review of all NSCLC patients seen at a single institution from January 2007 to January 2008 was performed. Various clinical and pathology data were collected. In BM patients, skeletal related events (SRE), interventions and outcomes were recorded. RESULTS We identified 383 patients; median age 68 (IQR 60-76); 54% female. Initially 156 patients (41%) were treated with curative intent of whom 91 subsequently relapsed; 227 (59%) were considered palliative from time of diagnosis, including 22 with early stage disease not amenable to radical therapy. Of 296 patients with advanced NSCLC, common metastatic sites were: lung/pleura (80%), mediastinal nodes (69%), bone (39%), brain (30%), and liver (24%). Of 118 patients with BM, 69 (59%) had ≥1 SREs (range 1-18). Common SREs were radiotherapy (63%), pathologic fractures (22%), spinal cord compression (6%) or surgery to bone (5%). Opioid analgesia was required in 69% of BM patients, only 6% of patients with BM received BTA. Overall survival (OS) in pts with mNSCLC was 7.3 months (IQR 3.1-20.5). Pts with BM had significantly shorter OS compared to those without BM (5.8 versus 10.2 months, p=0.03). CONCLUSIONS BM are common in patients with advanced NSCLC and associated with shorter survival. In this cohort, despite SREs occurred in many patients, BTA were rarely used.

Oral care and the use of bone-targeted agents in patients with metastatic cancers: A practical guide for dental surgeons and oncologists

Background Bone-targeted agents such as bisphosphonates and the RANKL antibody have revolutionised the care of patients with bone metastases. There has, however been increasing concern about the oral health of these patients and in particular osteonecrosis of the jaw (ONJ), especially with the increasing use of these agents at higher potencies for greater periods of time. Methods A review of the published data in PubMed and meeting abstracts was performed to examine incidence, risk factors, pathogenesis, clinical course and management of osteonecrosis of the jaw with focus on cancer patients treated with bone-targeted agents (BTA) for bone metastases. This manuscript takes the most frequent and pertinent questions raised by oncologists, dentists and oral and maxillofacial surgeons and tries to give a pragmatic overview of the literature. Results The incidence of ONJ varies depending on types of bone-targeted agents, duration of treatment and additional risk factors. The causes and pathogenesis of ONJ is not fully elucidated, however bone-targeted therapy induced impaired bone remodelling, microtrauma secondary to jaw activity, and oral bacterial infection seem to be important factors. Since the treatment options for ONJ are limited and not well established, preventive strategies have to be included in patients management. Conclusions Many unanswered questions remain about the optimal oral care of patients receiving bone-targeted agents. Prospective data collection will remedy this and help to provide practical guidelines for the management and treatment of those patients that require dental intervention.

A national portfolio of bone oncology trials—The Canadian experience in 2012

Background The impact of both cancer and its treatment on bone is an essential component of oncological practice. Bone oncology not only affects patients with both early stage and metastatic disease but also covers the entire spectrum of tumour types. We therefore decided to review and summarise bone oncology-related trials that are currently being conducted in Canada. Method We assessed ongoing and recently completed trials in Canada. We used available North American and Canadian cancer trial websites and also contacted known investigators in this field for their input. Results Twenty seven clinical trials were identified. Seven pertained to local treatment of bone metastasis from any solid tumour type. Seven were systemic treatment trials, five focused on bone biology and predictive factors, three evaluated safety of bone-targeted agents, three were adjuvant trials and two trials investigated impact of cancer therapy on bone health. The majority of trials were related to systemic treatment and bone biology in breast cancer. Most were small, single centre, grant-funded studies. Not surprisingly the larger safety and adjuvant studies were pharmaceutical company driven. Discussion Despite the widespread interest in bone-targeted therapies our survey would suggest that most studies are single centre and breast cancer focused. If major advances in bone oncology are to be made then collaborative strategies are needed to not only increase current sample sizes but to also expand these studies into non-breast cancer populations.

Identifying an optimal antiemetic regimen for patients receiving anthracycline and cyclophosphamide-based chemotherapy for breast cancer – An inspection of the evidence base informing clinical decision-making

BACKGROUND Despite consensus recommendations for antiemetics in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy, control of chemotherapy-induced nausea and vomiting (CINV) remains sub-optimal. OBJECTIVE To inspect available evidence from randomized controlled trials (RCT) in this population to establish treatment comparisons that have been studied, outcomes that have been reported, and the extent of study heterogeneity. Review of this data helps identify challenges for a systematic review comparing antiemetic regimens, and to identify potential future trials. METHODS A search of Ovid MEDLINE®, Embase and Cochrane CENTRAL was performed. We sought RCTs comparing antiemetic regimens in breast cancer patients receiving anthracycline and cyclophosphamide-based chemotherapy. We extracted information related to study design, patient characteristics and interventions compared. Patterns of outcome reporting were studied. While performing network meta-analysis was also of interest, studies were judged highly heterogeneous and it was felt findings from such work would be of uncertain validity. RESULTS From 1062 citations, a total of 30 full texts were retained. Overall, 47 antiemetic regimens were evaluated using 15 different CINV endpoints. Treatment comparisons were diverse and many were informed by single small trials. Reporting of key endpoints was varied and all endpoints were not consistently available. Heterogeneity in patients, chemotherapies administered, and intervention doses were noted. CONCLUSIONS Despite the availability of consensus recommendations for antiemetic use, we identified challenges in synthesizing the evidence base including high diversity in treatment comparisons, varied outcome reporting, and study heterogeneity. These represent challenges to identifying an optimal antiemetic regimen. Future antiemetic trials should incorporate more informed comparator selection, report patient-oriented outcomes in a standard fashion, and provide accessible data for these measures.

Bone-targeted agent use for bone metastases from breast cancer and prostate cancer: A patient survey.

Background In order to design studies assessing the optimal use of bone-targeted agents (BTAs) patient input is clearly desirable. Methods Patients who were receiving a BTA for metastatic prostate or breast cancer were surveyed at two Canadian cancer centres. Statistical analysis of respondent data was performed to establish relevant proportions of patient responses. Results Responses were received from 141 patients, 76 (53.9%) with prostate cancer and 65 (46.1%) with breast cancer. Duration of BTA use was <3 months (15.9%) to >24 months (35.2%). Patients were uncertain how long they would remain on a BTA. While most felt their BTA was given to reduce the chance of bone fractures (77%), 52% thought it would slow tumour growth. Prostate patients were more likely to receive denosumab and breast cancer patients, pamidronate. There was more variability in the dosing interval for breast cancer patients. Given a choice, most patients (49–57%) would prefer injection therapy to oral therapy (21–23%). Most patients (58–64%) were interested in enrolling in clinical trials of de-escalated therapy. Conclusion While there were clear differences in the types of BTAs patients received, our survey showed similarity for both prostate and breast cancer patients with respect to their perceptions of the goals of therapy. Patients were interested in participating in trials of de-escalated therapy. However, given that patients receive a range of agents for varying periods of time and in different locations (e.g. hospital vs. home), the design of future trials will need to be pragmatic to reflect this.

Histomorphometric and microarchitectural analyses using the 2 mm bone marrow trephine in metastatic breast cancer patients–preliminary results

Background Bone-targeted agents are widely used for the treatment of osteoporosis, the prevention of cancer-therapy induced bone loss, and for reducing the risk of skeletal related events in patients with metastatic disease. Despite widespread use, relatively little is known about the in vivo effect of these agents on bone homeostasis, bone quality, and bone architecture in humans. Traditionally bone quality has been assessed using a transiliac bone biopsy with a 7 mm “Bordier” core needle. We examined the possibility of using a 2 mm “Jamshidi” core needle as a more practical and less invasive method to assess bone turnover and potentially other tumor effects. Methods A pilot study on the feasibility of assessing bone quality and microarchitecture and tumor invasion using a 2 mm bone marrow trephine was conducted. Patients underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for bone microarchitecture, bone density, and histomorphometry. The study plan was to accrue three patients with advanced breast cancer to assess the feasibility of the study before enrolling more patients. Results The procedure was well tolerated. The sample quality was excellent to analyze bone trabecular microarchitecture using both microCT and histomorphometry. Intense osteoclastic activity was observed in a patient with extensive tumor burden in bone despite intravenous bisphosphonate therapy. Discussion Given the success of this study for assessing bone microarchitecture, bone density, and histomorphometry assessment using a 2 mm needle the study will be expanded beyond these initial three patients for longitudinal assessment of bone-targeted therapy.

Evaluating the feasibility of performing window of opportunity trials in breast cancer.

Background. The waiting period to surgery represents a valuable “window of opportunity” to evaluate novel therapeutic strategies. Interventional studies performed during this period require significant multidisciplinary collaboration to overcome logistical hurdles. We undertook a one-year prospective window of opportunity study to assess feasibility. Methods. Eligible newly diagnosed postmenopausal, estrogen receptor positive breast cancer patients awaiting primary surgery received anastrozole daily until surgery. Feasibility was assessed by (a) the proportion of patients who consented and (b) completed the study. Comparison of pre- and poststudy Ki67 labelling index and cleaved caspase 3 scores (CC3) was performed. Results. 22/131 (16.8%) patients were confirmed eligible and 20/22 (91%) patients completed the study. 19/20 (95%) patients agreed to undergo optional additional tissue biopsies. The mean duration of anastrozole use was 24.7 (15–44) days. There were a statistically significant decline in mean Ki67 indices of 48.8% (p < 0.001) and a trend towards significance in the decline of CC3 (p = 0.17) when comparing pre- with posttreatment values. Conclusion. window of opportunity trials in breast cancer are a feasible way of assessing the biologic efficacy of different therapies in the presurgical setting. The majority of eligible women were willing to participate including undergoing additional tissue biopsies.