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

PURPOSE: The 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: Optimisation 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.

Treatment of taxane acute pain syndrome (TAPS) in cancer patients receiving taxane-based chemotherapy-a systematic review.

BACKGROUND: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 1-3 days and lasting 5-7 days after taxane-based chemotherapy. Despite negatively impacting patient's quality of life, little is known about the optimal TAPS management. A systematic review of treatment strategies for TAPS across all tumor sites was performed. METHODS: Embase, Ovid MEDLINE(R), and the Cochrane Central Register of Controlled Trials were searched from 1946 to October 2014 for trials reporting the effectiveness of different treatments of TAPS in cancer patients receiving taxane-based chemotherapy. Two individuals independently screened citations and full-text articles for eligibility. Outcome measures included type of treatment and response of myalgias, arthralgias, pain, and quality of life (QoL). RESULTS: Of 1614 unique citations initially identified, five studies met the pre-specified eligibility criteria. Two were randomized placebo-controlled trials (225 patients), two were randomized open-label trials 76 patients), and one was a retrospective study (10 patients). The agents investigated included gabapentin, amifostine, glutathione, and glutamine. Study sizes ranged from 10 to 185 patients. Given the heterogeneity of study designs, a narrative synthesis of results was performed. Neither glutathione (QoL, p = 0.30, no 95 % CI reported) nor glutamine (mean improvement in average pain was 0.8 in both treatment arms, p = 0.84, no 95 % CI reported) were superior to placebo. Response to amifostine (pain response) and gabapentin (reduction in taxane-induced arthralgias and myalgias) was 36 % (95 % CI, 16-61 %) and 90 % (no 95 % CI data reported), respectively. CONCLUSIONS: Despite its prevalence in patients receiving taxane-based chemotherapies, TAPS remains poorly researched and few studies evaluate its optimal management. If the management of patients is to be improved, more prospective trials are needed.

Taxane acute pain syndrome (TAPS) in patients receiving taxane-based chemotherapy for breast cancer-a systematic review.

BACKGROUND: Taxane acute pain syndrome (TAPS) is characterized by myalgias and arthralgias starting 24-48 h after taxane-based chemotherapy and lasting for 5-7 days. Relatively little is known about its incidence and impact on quality of life. OBJECTIVES: A systematic review was conducted evaluating the incidence of TAPS in breast cancer patients receiving taxane-based chemotherapy. METHODS: Embase, Cochrane, and Ovid MEDLINE were searched from 1947 to July 2015. Data was sought from randomized controlled trials (RCTs), prospective and retrospective observational studies. Two reviewers independently screened citations and full text articles. Outcomes of interest were the incidence of TAPS and its impact on quality of life. RESULTS: Of 980 citations identified, 51 relevant studies (27,007 patients) were included. Data came from RCTs (12,357 patients), retrospective (6566 patients) and prospective observational studies (6210 patients). Study sample sizes ranged from 14 to 4149 patients (median 152). Given the significance between study heterogeneity, a meta-analysis was not performed. The incidence of TAPS varied between taxanes: paclitaxel (median 13.1 %, range 0.9-86 %), docetaxel (median 10.5 %, range 3.6-70 %), and nab-paclitaxel (26 %, range 14-43 %). In the metastatic setting, median incidence was 30 % (range 5.4-73 %), compared with 11.3 % (range 0.9-86 %) in the adjuvant setting. Three out of eight studies assessing quality of life demonstrated pain interference with daily activities. CONCLUSIONS: The incidence of TAPS varies between taxanes, regimens, and disease settings. In order to identify patients at the greatest risk of TAPS, and hence optimize its prevention and management, standardized methods of diagnosing and measuring TAPS are needed.

Issues Affecting the Loco-regional and Systemic Management of Patients with Invasive Lobular Carcinoma of the Breast.

Invasive lobular carcinoma (ILC) of the breast is the second most common type of invasive breast carcinoma accounting for 8-14% of all breast cancers. Traditional management of ILC has followed similar paradigms as that for invasive ductal carcinoma (IDC). However, ILC represents a pathologically, clinically and biologically unique variant of breast cancer with particular management challenges. These challenges are seen in both the loco-regional management of ILC; where ILC tumors tend to avoid detection and hence present as more clinically advanced and surgically challenging carcinomas, and the systemic management with a unique response pattern to standard systemic therapies. Because of these challenges, the outcome for patients with ILC has likely lagged behind the continued improvements seen in outcome for patients with IDC. Here, we discuss some of the unique challenges ILC presents and discuss possible management strategies to best overcome the difficulties in the loco-regional and systemic management of patients with ILC.

Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review.

BACKGROUND: Many cancer patients receive supplemental ascorbate (vitamin C) in the belief that it synergizes the anticancer effects of chemotherapy and reduces its toxicity. METHODS: A systematic review was performed to evaluate the antitumor effects and toxicity of ascorbate treatment. Medline (1946 to March 2014), EMBASE (1947 to March 2014), and the Cochrane central register (1993 to March 2014) were searched for randomized and observational studies. RESULTS: Of 696 identified records, 61 full-text articles were screened and 34 were included. In total, 5 randomized controlled trials (RCTs) (n = 322), 12 phase I/II trials (n = 287), 6 observational studies (n = 7,599), and 11 case reports (n = 267) were identified. Because of study heterogeneity, no meta-analyses were performed. No RCTs reported any statistically significant improvements in overall or progression-free survival or reduced toxicity with ascorbate relative to control arm. Evidence for ascorbate's antitumor effects was limited to case reports and observational and uncontrolled studies. CONCLUSION: There is no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Given the high financial and time costs to patients of this treatment, high-quality placebo-controlled trials are needed.

Management of urogenital atrophy in breast cancer patients: a systematic review of available evidence from randomized trials.

Symptoms of urogenital atrophy are common in breast cancer survivors. Its optimal management is currently unknown. A systematic review of randomized controlled trials (RCTs) evaluating treatments for urogenital atrophy in breast cancer patients was performed. EMBASE, Ovid Medline and the Cochrane Library were searched from 1946 to November 2014. Outcomes included improvements in both vaginal symptoms (e.g., dryness, pain, dyspareunia and itching) and vaginal hormone response measured by validated scales [e.g., Vaginal Health Index (VHI) and Vaginal Maturation Index (VMI)]. Of 430 unique citations identified, 4 studies (n = 196) met inclusion criteria. Interventions included pH-balanced gel, Replens(®), lidocaine, Estring(®) and Vagifem(®). Sample sizes ranged from 7 to 98 patients. Given the heterogeneity of the studies, a narrative synthesis of results was performed. One study of 98 patients suggested that vaginal pH-balanced gel (mean VHI 5.00 ± 0.816, mean VMI 51.18 ± 3.753) was more efficient than placebo (VHI 16.98 ± 3.875, p < 0.001, VMI 47.87 ± 2.728, p < 0.001) at 12 weeks in providing vaginal symptom relief. In patients who used lidocaine, 90 % had reduced dyspareunia compared to saline in a study of 46 patients. Although increased serum estradiol occurred, both Estring(®) and Vagifem(®) were shown to improve quality of life and VMI in a study of seven patients. Treatment of urogenital atrophy remains a challenging issue and there is a paucity of RCT evidence addressing this knowledge gap. It is evident that more prospective trials are needed.

Optimisation of steroid prophylaxis schedules in breast cancer patients receiving docetaxel chemotherapy-a survey of health care providers and patients.

PURPOSE: Despite the widespread use of steroid prophylaxis schedules for breast cancer patients receiving docetaxel chemotherapy, questions still exist regarding their optimal use. We surveyed health care providers and patients about their experiences with steroid prophylaxis. METHODS: Two questionnaires were developed and circulated. One was presented to health care providers (chemotherapy nurses, pharmacists and medical oncologists) involved in the treatment of breast cancer and the second to patients who had received docetaxel chemotherapy for early stage breast cancer. RESULTS: The health care providers' questionnaire was completed by 184 of 698 invitees: 92/171 (53.8 %) chemotherapy nurses, 56/284 (19.7 %) pharmacists and 36/243 (14.8 %) medical oncologists (overall response rate 26.4 %). Two steroid schedules were found to be the most commonly used: dexamethasone 8 mg BID for 6 doses, with either 3 (79 %) or 2 (11 %) doses taken before docetaxel administration. Suboptimal adherence to steroid premedication had been experienced by 98 % (177/181) of practitioners. Despite the presence of local treatment protocols in 65 % (119/183) of practitioners' institutions, 10 different strategies were commonly used when steroid premedication was taken incorrectly. The patients' questionnaire was completed by 72/87 (82.3 %) invitees. Respondents reported correctly taking their premedication 99 % (70/71) of the time. Patients felt steroids frequently caused side effects, the most common being sleep disturbance (35/72 = 49 %) and skin toxicity (16/72 = 22 %). CONCLUSION: Suboptimal adherence to steroid premedication prior to docetaxel administration is a common clinical challenge. There appears to be discordance between the practitioner and the patient experience. A single, universally accepted and used protocol for both pre- and post-medication and management when premedication is not taken as prescribed could improve adherence.

Defining optimal control of chemotherapy-induced nausea and vomiting-based on patients' experience.

PURPOSE: A considerable challenge when comparing antiemetic trials for chemotherapy-induced nausea and vomiting (CINV) is the large number of outcome measures for nausea and vomiting. The objective of this study is to determine the optimal definition of CINV control from the patients' perspective. METHODS: Patients with early-stage breast cancer who had received anthracycline-cyclophosphamide-based chemotherapy were surveyed. They were asked about their experiences of CINV and perceptions of different CINV assessment tools. RESULTS: Of 201 patients approached, 168 (83 %) completed the survey. Patients consistently ranked nausea over vomiting as the "worst side effect from chemotherapy." Despite the use of multi-agent antiemetic regimens, 71 % of patients experienced nausea and 26 % vomiting. Only 57 % of patients with any nausea or vomiting took rescue medications and only then when the symptom was severe. Most (76 %) patients believed that the primary end point of antiemetic trials should include the absence of both nausea and vomiting. Patients felt that CINV should be evaluated for the overall period post chemotherapy (i.e., days 1-5) and not simply the acute (the first 24 h) or delayed (days 2-5) periods. CONCLUSIONS: Patients strongly favored a CINV end point that includes the absence of both nausea and vomiting. Patients' experience with CINV is underestimated when nausea is not included in composite end points. "Use of rescue medication," a commonly used surrogate for emesis control, is inappropriate as it underestimates nausea. A standardized primary end point that includes nausea is essential if CINV control is to be improved.

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

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.

Bone-targeted therapy use in patients with bone metastases from lung cancer: A systematic review of randomized controlled trials.

BACKGROUND: Patients with advanced lung cancer commonly have bone metastases. Compared with other malignancies, the use of bone-targeted agents (e.g. bisphosphonates and denosumab) is less common in lung cancer patients. This may be due to the perception that bone-targeted agents are less effective in this population. OBJECTIVE: To perform a systematic review to evaluate data from randomized trials of bone-targeted agents in lung cancer patients with bone metastases. METHODS: A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials through May 2015 was performed. Randomized trials of bone-targeted therapies in lung cancer patients with bone metastases were sought. Outcomes studied included skeletal related events (SREs), pain, quality of life, progression-free survival and overall survival. Random effects meta-analyses were planned if studies were judged homogeneous. RESULTS: Of 632 abstracts, 17 publications describing 13 studies were included. Sample sizes ranged between 50 and 1776. Of 3379 patients, 1903 had lung cancer, with subgroup data available for 8 of 13 studies. Patient demographics were comparable, but enrollment criteria and endpoints were heterogeneous across studies, precluding meta-analysis. Study-specific results suggested that bone-modifying agents reduce the incidence of SREs and bone pain in lung cancer patients. Three studies suggested a survival benefit. CONCLUSION: Data from included trials suggests benefit of bone-targeted agents in lung cancer for the prevention of SREs and bone pain. There is a trend toward improvement in overall survival and progression-free survival, although further research is needed. Impact on quality of life and key subgroups for benefit both require future research.

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.

Are adjuvant bisphosphonates now standard of care of women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New Updates meeting.

The 9th Bone and the Oncologist New Updates conference was held in Ottawa, Canada during 2014. This annual meeting focuses on innovative research into the mechanisms and consequences of treatment-induced and metastatic bone disease. Given the recent presentation of the Oxford overview's "Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials" at the San Antonio Breast Cancer Symposium, a debate as to the pro's and con's of adjuvant bisphosphonate use in early stage breast cancer was undertaken. As bisphosphonate treatment in post-menopausal women appeared to demonstrate a similar magnitude of benefit to that of other commonly used adjuvant strategies the debate assessed whether or not there was sufficient data to incorporate adjuvant bisphosphonates into standard practice and if so, in which patient populations.

Treatment choices for patients with invasive lobular breast cancer: a doctor survey.

RATIONALE, AIMS AND OBJECTIVES: Invasive lobular breast cancer (ILC) has distinct features that present challenges for management. We surveyed doctors regarding management approaches, opinions on quality of evidence supporting their practice, and future research needs. METHODS: An online questionnaire was developed and circulated to breast cancer surgical, radiation and medical oncologists. RESULTS: The questionnaire was completed by 88/428 doctors (20.6%); 22/56 (39.3%) surgeons, 21/64 (32.8%) radiation oncologists and 45/308 (14.6%) medical oncologists. The majority (65%) of surgeons were comfortable treating ILC patients using the same surgical management as patients with invasive ductal cancers (IDC). Furthermore, 25% would perform a similar surgery but would obtain larger gross margins. There was equipoise for radiation oncologists regarding whether or not ILC was an independent risk factor for local-regional recurrence after either breast-conserving surgery or mastectomy. Of those radiation oncologists who believe ILC is an independent risk factor for recurrence after mastectomy, 44.4% would offer radiation in the absence of usual indications. Medical oncologists approached systemic therapy for ILC patients similarly to those with comparable IDCs. Areas identified as most controversial and requiring future research were preoperative magnetic resonance imaging, radiotherapy post-mastectomy and the responsiveness of ILC to adjuvant chemotherapy compared with endocrine therapy. CONCLUSIONS: There is a variation in doctors' beliefs, management and opinions regarding the quality of evidence for the management of ILC. Clinical trials specifically assessing the management of ILC are required to guide clinical practice.

Treatment for locally advanced breast cancer: a global challenge, personalized medicine or both?

In this special issue of Current Opinion in Supportive and Palliative Care, we are delighted to bring together key, internationally recognized experts in the field of breast cancer care for a special issue on locally advanced breast cancer (LABC). To place this disease in context, we have deliberately tried to keep the chapter headings pertinent to the real world issues facing both patients and their healthcare providers.

Long-term benefits versus side-effects from bone-targeted therapies for cancer patients: minimizing risk while maximizing benefits.

PURPOSE OF REVIEW: Bone-targeted therapies such as bisphosphonates and denosumab are established in the treatment of cancer patients to prevent or delay skeletal-related events and improve quality of life. Along with these benefits of bone-targeted therapies, there are also known risks and adverse effects. RECENT FINDINGS: Although historically bone-targeted therapy use has been limited to palliation in patients with bone metastases, recent evidence suggests that these agents may also have anti-cancer effects. This will likely lead to the greater use of these agents in patients with earlier-stage disease. Increased use will lead to more adverse effects. In particular, the risk of rare but severe toxicities will become important. SUMMARY: This article explores strategies to maximize the clinical benefit of such therapy while minimizing associated risks.

Definition and consequences of locally advanced breast cancer.

PURPOSE OF REVIEW: Locally advanced breast cancer (LABC) represents the most advanced stage breast cancer that is still potentially curable with surgery, radiation, and systemic therapy. The purpose of this review is to discuss LABC in the context of modern practice with a focus on its definition and potential consequences. RECENT FINDINGS: There is no one encompassing definition for this disease, but in general cancers of the breast are considered to be locally advanced if they are large and/or have infiltrated into adjacent tissues (the overlying skin or underlying muscles) and/or are found to have extensive locoregional lymph node involvement. It is not surprising, therefore, that LABC can cause significant morbidity and mortality. SUMMARY: Recent advances in our understanding of the biology of breast cancer have made it clear that LABC does not represent a single clinical entity but rather a heterogeneous group of breast tumors that share a common theme of extensive locoregional spread without overt evidence of distant metastatic disease. Despite advances in breast cancer screening and treatment LABC remains a significant global healthcare issue.

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.

Clinical practice guidelines and consensus statements in oncology--an assessment of their methodological quality.

BACKGROUND: Consensus statements and clinical practice guidelines are widely available for enhancing the care of cancer patients. Despite subtle differences in their definition and purpose, these terms are often used interchangeably. We systematically assessed the methodological quality of consensus statements and clinical practice guidelines published in three commonly read, geographically diverse, cancer-specific journals. Methods Consensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine's standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents. METHODS: Consensus statements and clinical practice guidelines published between January 2005 and September 2013 in Current Oncology, European Journal of Cancer and Journal of Clinical Oncology were evaluated. Each publication was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) rigour of development and editorial independence domains. For assessment of transparency of document development, 7 additional items were taken from the Institute of Medicine's standards for practice guidelines and the Journal of Clinical Oncology guidelines for authors of guidance documents. FINDINGS: Thirty-four consensus statements and 67 clinical practice guidelines were evaluated. The rigour of development score for consensus statements over the three journals was 32% lower than that of clinical practice guidelines. The editorial independence score was 15% lower for consensus statements than clinical practice guidelines. One journal scored consistently lower than the others over both domains. No journals adhered to all the items related to the transparency of document development. One journal's consensus statements endorsed a product made by the sponsoring pharmaceutical company in 64% of cases. CONCLUSION: Guidance documents are an essential part of oncology care and should be subjected to a rigorous and validated development process. Consensus statements had lower methodological quality than clinical practice guidelines using AGREE II. At a minimum, journals should ensure that that all consensus statements and clinical practice guidelines adhere to AGREE II criteria. Journals should consider explicitly requiring guidelines to declare pharmaceutical company sponsorship and to identify the sponsor's product to enhance transparency.