Mohammed Fk Ibrahim

Pharmacotherapy of bone metastases in breast cancer patients – an update

Introduction: Bone metastases in breast cancer patients are a common clinical problem and pose a threat to the quality of life of such patients. Multiple randomized trials have demonstrated the benefit of both bisphosphonates and denosumab in reducing the incidence and delaying the onset of skeletal related events (SREs) in breast cancer patients with bone metastases. Areas covered: We review the current literature on the use of bisphosphonates and denosumab along with strategies to maximize benefit and minimize risk of these agents. We also review potential future targets. Expert opinion: Despite the potent osteoclast inhibiting effects of the bone-targeted agents in current clinical use, we have likely maximized their ability to inhibit SREs and must in turn focus on minimizing their potential toxicity. The future will likely involve more novel treatment strategies as well as the development of new agents. The current ‘one size fits all’ approach for the management of breast cancer bone metastases will be replaced by ‘tailored’ treatment for each individual patient as we usher in the era of ‘personalized medicine.’ In addition, new bone-targeted agents (e.g., sclerostin inhibitors) and combinations will continue to be explored, as will the evaluation of the bone-targeting properties of more conventional non-osteoclast targeting therapies.

Optimal Management of Leptomeningeal Carcinomatosis in Breast Cancer Patients—A Systematic Review

The incidence of leptomeningeal carcinomatosis in breast cancer patients (LC-BC) is increasing. Despite significantly affecting patient quality of life (QoL) and overall survival (OS), little is known about its optimal management. A systematic review of treatment strategies for LC-BC was performed. EMBASE, Ovid Medline, Pubmed, and the Cochrane Central Register of Controlled Trials were searched from 1946 to 2015 for trials reporting on treatments for LC-BC. All treatment modalities and study types were considered. The outcome measures of interest included OS, time to neurologic progression (TTNP), QoL, and treatment toxicity. Of 718 unique citations, 173 studies met the prespecified eligibility criteria. Most were not specific to LC-BC patients. Of 4 identified randomized controlled trials (RCTs), 1 was specific to LC-BC patients and compared systemic therapy and involved-field radiotherapy with or without intrathecal (IT) methotrexate (35 patients), and the remaining 3 had compared different IT chemotherapy regimens (58 of 157 with LC-BC). Of the remaining studies, 19 were nonrandomized interventional studies (225 LC-BC patients), 148 were observational studies (3230 LC-BC patients), and 2 systematic reviews. Minimal prospective data were available on OS, TTNP, QoL, and toxicity. Owing to study heterogeneity, meta-analyses of the endpoint data could not be performed. Limited high-quality evidence exists regarding optimal treatment of LC-BC. The identified studies were heterogeneous and often methodologically poor. The only RCT that specifically assessed the role of IT chemotherapy showed no benefit, and, if anything, harm. Further prospective, tumor-specific trials with improved interstudy methodologic consistency and transparently reported data on OS, TTNP, QoL, and toxicity are urgently needed.

A Systematic Review of the Incidence and Risk Factors for Taxane Acute Pain Syndrome in Patients Receiving Taxane-Based Chemotherapy for Prostate Cancer

&NA; Taxane acute pain syndrome (TAPS) is characterized by myalgia and arthralgia starting 24 to 48 hours after taxane‐based chemotherapy and lasting ≤ 7 days. Little is known about its incidence and predisposing factors in patients with prostate cancer. A systematic review was performed to identify studies reporting the incidence and risk factors for TAPS in patients receiving taxane‐based chemotherapy for prostate cancer. Embase, Ovid Medline, and other nonindexed citations were searched from 1947 to July 7, 2015. Randomized trials and prospective observational studies reporting the outcomes for prostate cancer patients who had received taxane‐based chemotherapy were assessed. Four reviewers independently screened the citations and full text reports for data collection. Of 980 citations, 5 studies (2710 patients) met the eligibility criteria. The incidence of myalgia and arthralgia was reported in 4 trials (14%, [29% and 38%], 44.2%, and 46%). TAPS was not reported with cabazitaxel chemotherapy. Clinical risk factors were identified in 4 studies, suggesting that TAPS was numerically more common in the castrate‐resistant setting and when concurrent medications (eg, corticosteroids) were not used. Although the TAPS incidence has been poorly reported in clinical practice, the results of the present study suggest that arthralgia and myalgia are a common toxicity in patients with prostate cancer. An improved and universal definition of TAPS, patient‐directed reporting of TAPS, and improved standardized assessments are needed to better identify patients at the greatest risk of experiencing TAPS and improving patient care.

De-escalation of bone-targeted agents for metastatic prostate cancer

The Editor Current Oncology 10 September 2015 Despite advances in therapy, bone remains the most common site of prostate cancer recurrence. Once cancer has spread to bone, it is incurable and can be associated with pain, decreased quality of life, reduced mobility, and skeletal related events (sres). Given that more than half of all prostate cancer patients with bone metastases experience sres (for example, radiotherapy or surgery to bone, pathologic fractures, or spinal cord compression), reducing the occurrence of those events is an important therapeutic goal1. Currently, based on the results of several randomized trials, patients with bone metastases from castrate-resistant prostate cancer (mcrpc) are often treated with bone-targeted agents such as bisphosphonates or denosumab every 3–4 weeks. Historically, the dosing frequency for bone-targeted agents was adopted from data for the management of hypercalcemia of malignancy and for convenience (3- to 4-weekly dosing allowed clinicians to deliver the drugs at the same time that patients were receiving chemotherapy)1. However, that rationale ignores studies of biomarkers of bone turnover (a surrogate marker of sre risk), which have consistently shown, for both zoledronate and denosumab, rapid and sustained falls in turnover at significantly lower doses and for significantly longer than 3–4 weeks2. The question about the optimal dosing interval is particularly important given that the toxicity of bone-targeted agents is related to both the potency of the agent and the cumulative dose. A meta-analysis of de-escalated bone-targeted therapy (that is, treatment every 12 weeks instead of every 4 weeks) in patients with metastatic breast cancer was recently published. The results show no difference in sres or pain with de-escalated therapy3. Interest in similar de-escalated therapy for patients with mcrpc is now increasing. If de-escalated treatment is as efficacious as 3–4-weekly dosing, then not only would costs to both patients and the health care system be significantly reduced, but drug side effects could also potentially be reduced. In view of the findings in the breast cancer population, we conducted a systematic review to answer the question “Does 12-weekly bone-targeted agent use in mcrpc patients with bone metastases provide a benefit similar to that with 4-weekly treatment?” We were interested in randomized trials that had evaluated de-escalation of any established bone-targeted agent (for example, zoledronate and denosumab) against the standard 4-weekly treatment. Our systematic review was conducted as outlined in the Cochrane handbook, and only two studies met our inclusion criteria4,5. The study by Fizazi et al.4 was a phase ii open-label randomized trial in which 33 patients with mcrpc were randomized to either subcutaneous denosumab 180 mg every 4 weeks (n = 17) or every 12 weeks (n = 16). All patients randomized to denosumab had received treatment with zoledronic acid before randomization. Twenty-seven patients receiving denosumab completed the study. Bio-markers (urinary N-telopeptide) were assessed at week 13 and week 25. There was no significant difference between the 12-weekly and 4-weekly denosumab arms in terms of on-study biomarker changes, pain, or occurrence of sres. Those results are clearly interesting and similar to the findings in a similar population of breast cancer patients4; however, they are limited by the small sample size. The ongoing phase iii open-label randomized noninferiority reduse trial5 is comparing 4-weekly denosumab 120 mg with 12-weekly denosumab 120 mg in patients with bone metastases from breast cancer and mcrpc. The primary endpoint is time to first on-study symptomatic sre. The secondary endpoints include safety, time to subsequent on-study sre, quality of life, health economics, and bone turnover markers. Target accrual is 1380 patients; no data from the study are yet available. We have identified a knowledge gap in the existing literature that compares de-escalated with standard schedules of bone-targeted therapies in patients with bone metastases from crpc. More randomized trials are needed to compare the benefits and safety of de-escalated treatment. The study endpoints should include symptomatic sre rates, pain control, health-related quality of life, and safety, as well as health care costs. While waiting for the results of the reduse trial, researchers have a unique opportunity to perform additional practice-changing trials to identify the optimal schedule of denosumab dosing.

Enhancing accrual to chemotherapy trials for patients with early stage triple-negative breast cancer: a survey of physicians and patients

PurposeThe optimal chemotherapy regimen for patients with early stage triple-negative breast cancer (TNBC) remains unknown. The purpose of the study is to survey physicians and breast cancer patients about preferred chemotherapy regimens for early stage TNBC and clinical trial strategies.MethodsA standardised online questionnaire was developed and circulated to medical oncologists known to treat breast cancer. A separate questionnaire was given to patients who had received chemotherapy for breast cancer.ResultsThe questionnaire was completed by 41/84 medical oncologists (48.8% response rate) and 74 patients. The most commonly used neoadjuvant and adjuvant chemotherapy regimens for TNBC were dose-dense doxorubicin and cyclophosphamide (AC)–paclitaxel (P), dose-dense AC followed by weekly P and fluorouracil, epirubicin, cyclophosphamide–docetaxel (FEC-D). The majority of medical oncologists (80%) would be willing to enrol patients in trials evaluating the most effective chemotherapy regimen for TNBC. Oncologists favoured a three arm trial design comparing currently available standard of care treatments (36%) and trials of novel or non-standard of care agents 22% (9/41). Sixty percent (41/74) of patients indicated that they would be willing to be enrolled in trials evaluating various adjuvant regimens for TNBC. Both oncologists and patients were interested in novel consent approaches such as using the integrated consent model.ConclusionOptimisation of chemotherapy for TNBC is an important and unmet clinical need. It is apparent that various chemotherapy regimens are used for patients with early stage TNBC. The majority of medical oncologists and patients are interested in entering trials to optimise chemotherapy choices.

Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC)

PurposeOptimal primary febrile neutropenia (FN) prophylaxis (i.e. ciprofloxacin or granulocyte-colony stimulating factors [G-CSF]) for patients receiving docetaxel-cyclophosphamide (TC) chemotherapy is unknown. We assessed the feasibility of using a novel pragmatic comparative effectiveness trial to compare these standard-of-care options.MethodsEarly-stage breast cancer patients receiving TC chemotherapy were randomised to either ciprofloxacin or G-CSF. Trial methodology consists of broad eligibility criteria, simply-defined endpoints, integrated consent model incorporating oral consent, and web-based randomisation in the clinic. Primary feasibility endpoints included patient and physician engagement (if > 50% of patients approached agree to participate and if > 50% of physicians approached patients for the study). Secondary clinical endpoints included the following: first occurrence rates of FN, treatment-related hospitalisation, or chemotherapy dose reduction/delay/discontinuation, as well as patient satisfaction with the oral consent process.ResultsOf 204 patients approached, 91.2% (186/204) agreed to randomisation. Sixteen of twenty (80%) participating medical oncologists randomised patients. Median patient age was 57.7 (range 31.8–84.1). The 186 patients received 557 cycles of chemotherapy. Overall incidences of first events by patient (n = 186) were as follows: FN (18/186, 21.43%), treatment-related hospitalisation (11/186, 13.10%), chemotherapy reduction (19/186, 22.62%), chemotherapy discontinuation (16/186, 19.05%), and chemotherapy delays (5/186, 5.95%). A total of 37.77% (69/186) of patients and 12.39% (69/557) of chemotherapy cycles had at least one of these first events. Patients were highly satisfied with the oral consent process.ConclusionThis study met its feasibility endpoints. This model offers a means of comparing standard-of-care treatments in a practical and cost-efficient manner.Trial registrationTrial registration: ClinicalTrials.gov: NCT02173262

Future directions for bone metastasis research – highlights from the 2015 bone and the Oncologist new updates conference (BONUS)

In an era of reduced peer-reviewed grant funding, performing academic bone oncology-related research has become increasingly challenging. Over the last 10 years we have held an annual meeting to bring together clinicians, clinician/scientists and basic biomedical researchers interested in the effects of cancer and its treatment on skeletal tissues. In the past these “Bone and the Oncologist New Updates Conference (BONUS)” meetings have served as critical catalyst for initiating productive research collaborations between attendees. The 2015 BONUS meeting format focused on potential key research themes that could form the basis of a coordinated national research strategy to tackle unmet clinical and research needs related to complications associated with cancer metastasis to bone. The three themes planned for discussion were: Is bone metastases-related pain the main issue facing patients? Are there new therapeutic targets for patients with bone metastases? How do we more firmly link basic science with clinical practice? We present a summary of lectures and commentaries from the attendees to serve as an example that other similarly motivated groups can model and share their experiences. It is our hope that these presentations will result in comments, feedback and suggestions from all those researchers interested in this important area.

Strategies for obtaining bone biopsy specimens from breast cancer patients - Past experience and future directions.

Background Cancer and its treatment can have multiple effects on the bone. Despite the widespread use of in vivo and in vitro models, it is still necessary to understand these effects in humans. Obtaining human bone biopsies is technically challenging and in this article we review the experiences from the Ottawa Bone Oncology Program. Methods A series of bone biopsy studies in breast cancer patients with and without bone metastasis have been performed. We reviewed the results of these studies and present them in a descriptive manner. We discuss lessons learned from each project and how they have affected future directions for research. Results Since 2009, 5 studies have been performed accruing 97 breast cancer patients. Study endpoints have ranged from comparing the yield of malignant cells from CT-guided versus standard iliac crest biopsies, to studies assessing the feasibility of micro-CT analysis on Jedhadi trephines to evaluate bisphosphonate effects on bone micro-architecture. More recently, we have assessed the feasibility of performing repeat bone biopsies in the same patient as well as evaluating the practicality of obtaining bone tissue at the time of orthopaedic surgery. Conclusion Human bone tissue is an important biological resource. Our experience suggests that obtaining bone biopsies is feasible and can yield adequate amount of tumour cells for many studies. However, these remain technically challenging specimens to obtain and given the rapid advances in cancer therapeutics and the use of potent adjuvant bone-targeted agents, more centres need to be involved in these types of studies.