Does Pre-Emptive Availability of PREDICT 2.1 Results Change Ordering Practices for Oncotype DX? A Multi-Center Prospective Cohort Study.

For early-stage hormone receptor (HR)-positive and HER2-negative breast cancer, tools to estimate treatment benefit include free and publicly available algorithms (e.g., PREDICT 2.1) and expensive molecular assays (e.g., Oncotype DX). There remains a need to identify patients who de-rive the most benefit from molecular assays and where this test may be of poor value. In this multicenter prospective cohort study, we evaluated whether use of PREDICT 2.1 would impact physician decision making. For the first 6 months of the study, data on physician use of both PREDICT 2.1 and Oncotype DX ordering were collected on all newly diagnosed patients eligible for molecular testing. After 6 months, an educational intervention was undertaken to see if providing physicians with PREDICT 2.1 results affects the frequency of Oncotype DX requests. A total of 602 patients across six cancer centers in Ontario, Canada were recruited between March 2020 and November 2021. Providing PREDICT 2.1 results and an educational intervention did not alter the ordering of an Oncotype DX. For patients with low clinical risk, either by clinico-pathologic features or by PREDICT 2.1, the probability of obtaining a high Oncotype DX recurrence score was substantially lower compared to patients with high-clinical-risk disease. The introduction of an educational intervention had no impact on molecular assay requests. However, routine ordering of molecular assays for patients with low-clinical-risk disease is of poor value.

A case of splenic artery aneurysm and rupture in a patient on a vascular endothelial growth factor inhibitor for renal cell carcinoma.

BACKGROUND: Pazopanib is a vascular endothelial growth factor inhibitor that is used in the treatment of metastatic renal cell carcinoma. Post market reports demonstrate an increasing awareness of the association of arterial aneurysms and dissections with vascular endothelial growth factor inhibitor use, although, few reports exist for pazopanib. CASE: Here we report a 69-year-old patient with minimal cardiovascular risk factors who developed a rupture of a splenic arterial aneurysm after more than 5 years of effective treatment with pazopanib for metastatic renal cell carcinoma. CONCLUSION: This case report outlines the necessity to monitor patients while on pazopanib, even when there are minimal risk factors and long periods of tolerance.

The current landscape of systemic therapy for recurrent glioblastoma: A systematic review of randomized-controlled trials.

AIM: Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM). METHODS: We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment. RESULTS: 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3 to 17.6 months. CONCLUSIONS: Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512.

Diagnostic assessment program for prostate cancer: Lessons learned after 2 years and degree of compliance to Canadian guidelines.

BACKGROUND: In 2018, our Institute launched the Diagnostic Assessment Program (DAP) for prostate cancer. It enabled quick access to a urologist for patients presented to family physician with elevated PSA and allowed fast multidisciplinary patient care. We aim to document our data over 2 years in comparison to data before implementation of DAP and its impact on the degree of adherence to Canadian guidelines. METHODS: From April 2016 to April 2020, 880 patients who were evaluated for prostate cancer at Thunder Bay Regional Health Sciences Centre (TBRHSC) were included in this study. Patients' characteristics, clinical data, waiting times and line of treatment before and after implementation of DAP were calculated and statistically analysed. RESULTS: The median waiting time to urology consultation was significantly reduced from 68 (IQR 27-168) days to 34 (23-44) days (p < 0.001). The time from patient's referral to prostate biopsy decreased substantially from 34 (20-66) days to 18(11- 25) days after DAP (p < 0.001). After DAP, the percentage of Gleason 6 detected prostate cancers were significantly increased (19.7% to 30%) (p = 0.02). After DAP, rate for intermediate-risk patients elected for external beam radiotherapy (from 53.5% to 57.9%, p = 0.53) and radical prostatectomy (from 34.5% to 39.4%, p = 0.47) increased. More compliance to Canadian guidelines was observed in intermediate risk patients (88% vs 97.3%, p =.008). CONCLUSIONS: Implementation of DAP has led to a notable reduction of waiting time to urology consult and prostate biopsy. There is significant increase in Gleason 6 detected prostate cancer. Increased compliance to Canadian guidelines was detected in intermediate risk patients.

Does the Time of Day at Which Endocrine Therapy Is Taken Affect Breast Cancer Patient Outcomes?

BACKGROUND: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. LITERATURE REVIEW: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. CONCLUSIONS: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41-72% and 31-73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.

A multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia.

BACKGROUND: Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. METHODS: EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. RESULTS: 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = -6.7%, 95%CI = -13.5%-0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained. CONCLUSION: The primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective.

The COVID-19 pandemic: An opportunity to rethink and harmonise the frequency of follow-up visits for patients with early stage breast cancer.

PURPOSE: While routine, in-person follow-up of early-stage breast cancer patients (EBC) after completion of initial treatment is common, the COVID-19 pandemic has resulted in unprecedented changes in clinical practice. A systematic review was performed to evaluate the evidence supporting different frequencies of routine follow-up. METHODS: MEDLINE and the Cochrane Collaboration Library were searched from database inception to July 16, 2020 for randomized controlled trials (RCTs) and prospective cohort studies (PCS) evaluating different frequencies of routine follow-up. Citations were assessed by pairs of independent reviewers. Risk of Bias (RoB) was assessed using the Cochrane RoB tool for RCTs and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. Findings were summarized narratively. RESULTS: The literature search identified 3316 studies, of which 7 (6 RCTs and 1 PCS) were eligible. Study endpoints included; quality of life (QoL; 5 RCTs and 1 PCS), disease free survival (DFS) (1 RCT), overall survival (OS) (1 RCT) and cost-effectiveness (1 RCT). The results showed reduction in follow-up frequency had no adverse effect on: QoL (6 studies, n = 920), DFS (1 trial, n = 472) or OS (1 trial, n = 472), but improved cost-effectiveness (1 trial, n = 472). Four RCTs specifically examined follow-up on-demand versus scheduled follow-up visits and found no statistically significant differences in QoL (n = 544). CONCLUSION: While no evidence-based guidelines suggest that follow-up of EBC patients improves DFS or OS, routinely scheduled in-person assessment is common. RCT data suggests that reduced frequency of follow-up has no adverse effects.

Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review.

PURPOSE: Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1-2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted. METHODS: MEDLINE, Embase, and Cochrane databases were searched (1970-February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years. RESULTS: Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0-24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8-18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare. CONCLUSIONS: Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed. PROSPERO REGISTRATION NUMBER: CRD42019126813.

Does integration of Magee equations into routine clinical practice affect whether oncologists order the Oncotype DX test? A prospective randomized trial.

OBJECTIVE: The three Magee Equations provide an estimate of the Oncotype DX recurrence score using commonly available clinicopathologic information (tumour size, grade, oestrogen receptor, progesterone receptor, HER2, and Ki67). We assessed whether integration of Magee Equations into routine clinical practice affected the frequency of Oncotype DX requests. METHODS: Patients with newly diagnosed, node negative, hormone receptor positive, and HER2 negative invasive breast cancer were randomized to undergo a Magee calculation or not. At the first clinic assessment, the oncologist was provided with all routinely available clinicopathologic information (including Ki67) either with or without the results of Magee Equations. Primary outcome was frequency of Oncotype DX ordering. Secondary outcomes included frequency of chemotherapy use, time to commencement of radiotherapy, or systemic therapy. Physician comfort with systemic therapy choices and the use of Ki67 and Magee Equations was also assessed. RESULTS: Data from 175 randomized patients was available, 84 patients (48%) with and 91 (52%) without calculated Magee Equations. Oncotype DX was ordered in 10 (12.05%) and 13 (14.44%) (RR 0.83, 0.39-1.80; P = 0.64) in the Magee and no Magee groups, respectively. There were no statistically or clinically significant differences between the randomized groups for any of the secondary outcomes. Availability of both Ki67 and Magee Equations was associated with increased physician comfort around systemic treatment decisions. CONCLUSIONS: In a practice where Ki67 is routinely available, addition of Magee Equations into routine clinic practice was not associated with a reduction in Oncotype DX use. Availability of both Ki67 and Magee Equations did however increase physician comfort with systemic therapy decisions.

A multi-center pragmatic, randomized, feasibility trial comparing standard of care schedules of filgrastim administration for primary febrile neutropenia prophylaxis in early-stage breast cancer.

INTRODUCTION: The most effective duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer (EBC) patients is unknown. Despite significant differences in cost and toxicity, no prospective trial has been performed to optimize practice. We assessed the feasibility of using a novel pragmatic trial model to compare the most commonly used schedules of filgrastim. METHODS: Early breast cancer patients receiving chemotherapy were randomized to 5, 7, or 10 days of filgrastim as primary FN prophylaxis. The trial methodology integrated broad eligibility criteria, simply defined endpoints, an integrated consent model incorporating oral consent, and web-based randomization in the clinic. Feasibility was reflected through a combination of primary endpoints including patient and physician engagement (if > 50% of appropriate patients approached agree to participate, and if > 50% of physicians approached patients for the study). Secondary endpoints included the first occurrence rates of FN, treatment-related hospital admission, or chemotherapy dose reductions/delays/discontinuation. RESULTS: From May 2015 to August 2016, 142/149 (95.3%) patients approached agreed to participate and were randomized. Seventeen of 24 (70.8%) medical oncologists approached and randomized patients. The 142 patients received a total of 495 cycles of chemotherapy. Aggregate incidences of a first event by patient were FN (8/142, 5.6%), treatment-related hospitalization (6/142, 4.2%), chemotherapy discontinuation (7/142, 4.9%), chemotherapy delays (5/142, 3.5%), and chemotherapy dose reduction (18/142, 12.7%). Overall, 31.7% (45/142) of patients and 9.0% (45/495) of chemotherapy cycles were associated with one of these first events. CONCLUSION: This study met its feasibility endpoints. This novel pragmatic trial approach offers a means of comparing standard of care treatments in a practical and cost-effective manner. The trial will now be expanded to compare rates of FN between the three filgrastim schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02428114.

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.

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.

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.

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.

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.