Management of Uveal Melanoma: Updated Cancer Care Alberta Clinical Practice Guideline.

OBJECTIVE: The purpose of this guideline update is to reassess and update recommendations in the prior guideline from 2016 on the appropriate management of patients with uveal melanoma. METHODS: In 2021, a multidisciplinary working group from the Provincial Cutaneous Tumour Team, Cancer Care Alberta, Alberta Health Services was convened to update the guideline. A comprehensive review of new research evidence in PubMed as well as new clinical practice guidelines from prominent oncology groups informed the update. An enhancement in methodology included adding levels of evidence and strength of recommendations. The updated guideline was circulated to all members of the Provincial Cutaneous Tumour Team for review and endorsement. RESULTS: New and modified recommendations address provider training requirements, diagnostic imaging for the detection of metastases, neo-adjuvant pre-enucleation radiotherapy, intravitreal anti-vascular endothelial growth factor agents for radiation retinopathy, genetic prognostic testing, surveillance following definitive local therapy, and systemic therapy for patients with metastatic uveal melanoma. DISCUSSION: The recommendations represent evidence-based standards of care agreed to by a large multidisciplinary group of healthcare professionals.

Update to the Canadian clinical practice guideline for best-practice management of breast cancer-related lymphedema: study protocol.

BACKGROUND: One of the more frequent complications following treatment for breast cancer, lymphedema is a substantial swelling of the arm, breast and chest wall that occurs on the side where lymph nodes were removed. The aim of this work is to update recommendations on the prevention, diagnosis and management of lymphedema related to breast cancer. METHODS: We present the protocol for an update of the 2001 clinical practice guideline on lymphedema from the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. We will use a patient-oriented research approach with a focus on self-management and the positive health model to inform the updated guideline development. The methods proposed will be undertaken with consideration of the standards outlined in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The literature will be appraised by evaluating existing guidelines from other countries, the evidence from systematic reviews and meta-analyses and direct evidence from clinical studies. We will manage competing interests according to Guidelines International Network principles. Recommendations will be presented using an actionable statement format and will be linked to the level of evidence along with any relevant considerations used in formulation. A draft of the guideline will be produced by the steering committee then sent out to international experts and stakeholder groups for feedback. INTERPRETATION: The primary benefit of this clinical guideline will be to improve the quality of care of women with breast cancer-related lymphedema. Findings will be disseminated at national and international conferences and through webinars and educational videos hosted on the websites of the supporting organizations.

Breast reconstruction after therapeutic or prophylactic mastectomy for breast cancer: A comparison of guideline recommendations.

BACKGROUND: The purpose of this article is to illuminate differences in published clinical practice guideline recommendations for breast reconstruction after prophylactic and therapeutic mastectomy. METHODS: Ten guidelines were identified through a systematic search of websites and databases of reputable oncology guideline developers, and key differences and gaps in recommendations were noted. Quality assessment of the guidelines was conducted by three reviewers using the AGREE II tool, focusing on breast reconstruction specific documents rather than the general breast cancer guidelines. RESULTS: The most comprehensive guidelines were published by Alberta Health Services, Cancer Care Ontario, the American Society of Plastic Surgeons, and the Association of Breast Surgery/British Association of Plastic Reconstructive and Aesthetic Surgeons. AGREE II scores in the domains of "Scope and Purpose" and "Clarity and Presentation" were ranked relatively high for all four guidelines while "Applicability" and "Editorial Independence" were ranked relatively low. The Alberta and Ontario guidelines were the overall highest ranked guidelines across all domains. CONCLUSION: Overall, these guidelines provide consistent recommendations on who should receive breast reconstruction education, who is a candidate for postmastectomy breast reconstruction, and the appropriate timing of reconstruction and extent of mastectomy. Future updates from all should focus on expanding to include alloplastic and autologous forms of reconstruction and should include a broad scope of relevant questions.

Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer.

BACKGROUND: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes. PATIENTS AND METHODS: Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity. RESULTS: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes. CONCLUSIONS: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.

Real-World Outcomes of Adjuvant Chemotherapy for Node-Negative and Node-Positive HER2-Positive Breast Cancer.

Background: Comparative real-world outcomes for patients with HER2-positive (HER2+) breast cancer receiving adjuvant trastuzumab outside of clinical trials are lacking. This study sought to retrospectively characterize outcomes for patients with node-negative and node-positive breast cancer receiving adjuvant trastuzumab in combination with docetaxel/cyclophosphamide (DCH), docetaxel/carboplatin/trastuzumab (TCH), or fluorouracil/epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (FEC-DH) chemotherapy in Alberta, Canada, from 2007 through 2014. Methods: Disease-free survival and overall survival (OS) analyses for node-negative cohorts receiving DCH (n=111) or TCH (n=371) and node-positive cohorts receiving FEC-DH (n=146) or TCH (n=315) were compared using chi-square, Kaplan-Meier, or Cox multivariable analysis where appropriate. Results: Median follow-up was similar in node-negative (63.9 months) and node-positive (69.0 months) cohorts. The 5-year OS rates in patients with node-negative disease receiving DCH or TCH were similar (95.2% vs 96.9%; P=.268), whereas 5-year OS rates were higher but nonsignificant for patients with node-positive disease treated with FEC-DH compared with TCH (95.2% vs 91.4%; P=.160). Subgroup analysis of node-positive cohorts showed significantly improved OS with FEC-DH versus TCH in patients with estrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer (98.3% vs 91.6%, respectively; P=.014). Conversely, patients with ER/PR-negative disease showed a nonsignificant trend toward higher OS rates with TCH versus FEC-DH (91.6% vs 83.3%, respectively; P=.298). Given the retrospective design, we were unable to capture all potential covariates that may have impacted treatment assignment and/or outcomes. Furthermore, cardiac toxicity data were unavailable. Conclusions: Survival rates of patients with HER2+ breast cancer in our study are comparable to those seen in clinical trials. Our findings support chemotherapy de-escalation in patients with node-negative disease and validate the efficacy of FEC-DH in those with node-positive disease.

Assessing guideline impact on referral patterns of post-prostatectomy patients to radiation oncologists.

INTRODUCTION: Adjuvant radiotherapy (aRT) can improve biochemical progression-free survival in patients with high-risk features (HRF) after radical prostatectomy (RP). Guidelines from Alberta and the Genitourinary Radiation Oncologists of Canada (GUROC) recommend that patients with HRF be referred to radiation oncologists (RO) based on the findings from three randomized, controlled trials (RCT). Our study examines the impact of these recommendations both pre- (2005) and post- (2012) publication of RCT and GUROC guideline establishment. METHODS: Patients undergoing RP during 2005 and 2012 were identified from the provincial cancer registry. Charts were retrospectively reviewed and variables of interest were linked to the registry data. RO referral patterns for each year were determined and variables influencing referral (extracapsular extension, positive margin, seminal vesicle invasion, and post-RP prostate-specific antigen [PSA]) were compared. RESULTS: Median time to referral was 26.4 months in 2005 compared to 3.7 months 2012 (p<0.001). Among patients referred post-RP, a higher proportion was referred within six months in 2012 (21%) as compared to 2005 (13%) (p=0.003). Among eligible patients in 2012, 30% were referred for discussion of aRT compared to 24% in 2005 (p=0.003). There was a marked drop in patients referred for salvage radiation therapy beyond six months and a rise in the number of patients who are never referred. CONCLUSIONS: Despite an increase in referral rates to RO post-RP from 2005-2012, more than 50% of those patients with HRF did not receive a referral. Initiatives aimed at improving multidisciplinary care and guideline adherence should be undertaken.

Supporting Patients With Incurable Cancer: Backup Behavior in Multidisciplinary Cross-Functional Teams.

Caring for patients with incurable cancer presents unique challenges. Managing symptoms that evolve with changing clinical status and, at the same time, ensuring alignment with patient goals demands specific attention from clinicians. With care needs that often transcend traditional service provision boundaries, patients who seek palliation commonly interface with a team of providers that represents multiple disciplines across multiple settings. In this case study, we explore some of the dynamics of a cross-disciplinary approach to symptom management in an integrated outpatient radiotherapy service model. Providers who care for patients with incurable cancer must rely on one another to secure delivery of the right services at the right time by the right person. In a model of shared responsibilities, flexibility in who does what and when can enhance overall team performance. Adapting requires within-team and between-team monitoring of task and function execution for any given patient. This can be facilitated by a common understanding of the purpose of the clinical team and an awareness of the particular circumstances surrounding care provision. Backup behavior, in which one team member steps in to help another meet an expectation that would otherwise not be fulfilled, is a supportive team practice that may follow naturally in high-functioning teams. Such team processes as these have a place in the care of patients with incurable cancer and help to ensure that individual provider efforts more effectively translate into improved palliation for patients with unmet needs.

An audit of referral and treatment patterns of high-risk prostate cancer patients in Alberta.

INTRODUCTION: We aimed to determine the impact of clinical practice guidelines (CPG) on rates of radiation oncologist (RO) referral, androgen-deprivation therapy (ADT), radiation therapy (RT), and radical prostatectomy (RP) in patients with high-risk prostate cancer (HR-PCa). METHODS: All men >18 years, diagnosed with PCa in 2005 and 2012 were identified from the Alberta Cancer Registry. Patient age, aggregated clinical risk group (ACRG) score, Gleason score (GS), pre-treatment prostate-specific antigen (PSA), RO referral, and treatment received were extracted from electronic medical records. Logistic regression modelling was used to examine associations between RO referral rates and relevant factors. RESULTS: HR-PCa was diagnosed in 261 of 1792 patients in 2005 and 435 of 2148 in 2012. Median age and ACRG scores were similar in both years (p>0.05). The rate of patients with PSA >20 were 67% and 57% in 2005 and 2012, respectively (p=0.004). GS ≤6 was found in 13% vs. 5% of patients, GS 7 in 27% vs. 24%, and GS ≥8 in 59% vs. 71% in 2005 and 2012, respectively (p<0.001). In 2005, RO referral rate was 68% compared to 56% in 2012 (p=0.001), use of RT + ADT was 53% compared to 32% (p<0.001), and RP rate was 9% vs. 17% (p=0.002). On regression analysis, older age, 2012 year of diagnosis and higher PSA were associated with decreased RO referral rates (odds ratios [OR] 0.49, 95% confidence interval [CI] 0.39-0.61; OR 0.51, 95% CI 0.34-0.76; and OR 0.64, 95% CI 0.39-0.61), respectively [p<0.001]). CONCLUSIONS: Since CPG creation in 2005, RO referral rates and ADT + RT use declined and RP rates increased, which demonstrates a need to improve adherence to CPG in the HR-PCa population.

A population-based assessment of melanoma: Does treatment in a regional cancer center make a difference?

BACKGROUND: Regionalization of care to specialized centers has improved outcomes for several cancer types. We sought to determine if treatment in a regional cancer center (RCC) impacts guideline adherence and outcomes for patients with melanoma. METHODS: In Alberta, Canada, 561 patients with stage I-IIIC primary melanoma were diagnosed between January 2009 and December 2010. The electronic health record was used to capture demographic and pathologic data. Provincial guidelines for sentinel lymph node biopsy (SLNB) and wide local excision (WLE) are based on recommendations of several pre-existing guidelines including the National Comprehensive Cancer Network. RESULTS: 148 of 561 patients were identified as having been treated at a RCC. Median follow-up was 45 months. Patients treated at the RCC presented with higher stage melanomas. The RCC was more likely to follow guideline recommendations for performing SLNB (81.3% vs. 55.4%, P < 0.0001) but not for the extent of WLE (76.6% vs. 84.1%, P = 0.054). Overall survival was impacted by tumor thickness (HR 1.14, P < 0.0001), ulceration (HR 5.58, P < 0.0001), and mitoses (HR 0.59, P = 0.05). CONCLUSIONS: The RCC more closely followed guidelines for SLNB but not for WLE. Despite patients treated at the RCC presenting with a more advanced stage, overall survival and disease-free survival appear to not be affected by treatment center.

Comparative effectiveness analysis of different salvage therapy intensities used for diffuse large B-cell lymphoma in Northern or Southern Alberta: an instrumental variable analysis.

To date, no clinical trial has addressed salvage therapy intensity for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We sought to determine whether the more intensive salvage chemotherapy approach used in Southern Alberta (SAB) compared to the conventional dose salvage approach used in Northern Alberta (NAB) affects the rates of autologous stem cell transplant (ASCT) and survival in patients with relapsed DLBCL. Using instrumental variable analysis, we examined 147 consecutive patients with relapsed/refractory DLBCL from 2004 to 2010 who received salvage therapy in SAB (n = 70) or NAB (n = 77). Patients treated in SAB had higher rates of: salvage chemotherapy response (85.0% vs. 54.0%, p = 0.001), ASCT (61.4% vs. 41.6%, p = 0.016) and 4-year overall survival (41% vs. 20%, p = 0.002) than those in NAB, respectively. This study supports the hypothesis that selective use of intensive salvage chemotherapy leads to higher rates of ASCT and survival in this population.

Management of recurrent medulloblastoma in adult patients: a systematic review and recommendations.

Medulloblastoma accounts for almost one-third of pediatric central nervous system (CNS) cancers, but is very rare in the adult population. As a result, adult patients with medulloblastoma are often treated according to therapies developed for children with similarly staged disease at diagnosis, based on the assumption that adult and pediatric tumors have similar properties. The purpose of this review was to summarize the evidence and to make recommendations for the management of recurrent disease in adult patients with medulloblastoma. We conducted a systematic literature search to find publications addressing treatment of recurrent medulloblastoma in adults. Current treatment strategies for adult patients with relapsed medulloblastoma are based on the results of retrospective case series and published consensus recommendations, and include maximal safe re-resection where possible, combined with chemotherapy and/or re-irradiation. We describe the results of 13 publications involving 66 adult patients treated with high-dose chemotherapy (HDCT) plus stem cell transplantation for recurrent medulloblastoma. HDCT with stem cell transplantation may be a treatment option for a small proportion of adult patients who are unlikely to benefit from conventional chemotherapy and who are fit and have their disease recurrence contained within the CNS. Potential cases in which stem cell transplantation is being considered should be discussed at a multidisciplinary tumor board which includes involvement by hematologic oncologists and transplant specialists.

Is there a role for clinical practice guidelines in multidisciplinary tumor board meetings? A descriptive study of knowledge transfer between research and practice.

The aim of this study was to characterize practice patterns and decision-making processes of healthcare providers attending weekly neuro-oncology tumor board meetings, and to assess their familiarity with clinical practice guidelines (CPGs) in neuro-oncology. Members of the Neuro-Oncology Tumor Team at two tertiary cancer centers completed a web-based questionnaire assessing characteristics of weekly tumor board meetings and perceptions of CPGs. Twenty-three (66%) tumor team members responded. Diagnostic imaging results and interpretation, medical, surgical, and/or radiation treatment planning, and pathology results and interpretation were the most commonly identified aspects of patient care discussed at tumor board meetings, and almost all respondents indicated that these meetings were "very beneficial" to their own practice. When deciding on a treatment plan, respondents rely most on the clinical expertise of colleagues, medical literature, personal experience, active clinical trial protocols, and published CPGs. Opinions of the local CPGs varied considerably, and while 56% of respondents supported regular discussion of them during meetings, only 32% indicated that they were routinely reviewed. Updating the literature more frequently, implementing a formal grading system for the evidence, and incorporating clinical care pathways were the most frequently cited methods to improve the CPGs. Tumor board meetings are beneficial to the treatment planning process for neuro-oncology patients.

Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure.

BACKGROUND: Selective serotonin reuptake inhibitor antidepressants (SSRIs) and benzodiazepines are frequently used to treat maternal depression and anxiety disorders during pregnancy. Recent reports suggest that prenatal SSRI exposure is associated with a neonatal discontinuation syndrome. It remains unclear whether these symptoms are directly related to SSRI exposure alone or are due to concurrent pharmacologic factors. Also, this study explores relationships between neonatal outcomes and medication levels during pregnancy, at delivery, and in the newborn period. METHOD: This study sought to compare newborn behavior following second and third trimester exposure to either single-agent SSRIs (group 1) or SSRIs combined with clonazepam (group 2). A prospective cohort of mothers and their infants (N = 46) who had received SSRI medication alone or in combination with clonazepam were studied from June 1996 through June 2000 and compared with a nonexposed control group (N = 23). Infants were assessed in the newborn period for signs suggestive of a "discontinuation syndrome." Maternal drug levels were measured during the pregnancy and at delivery. Infant drug levels from cord blood and at day 2 of life were also obtained. RESULTS: Overall, 30% of the exposed infants (groups 1 and 2, N = 14) showed symptoms of transient poor neonatal adaptation compared with 9% (N = 2) of control infants. In group 1, 25% had symptoms (fluoxetine N = 3; paroxetine N = 3; sertraline N = 1) and in group 2, 39% of infants had symptoms (paroxetine with clonazepam, N = 7). Symptoms were typically mild respiratory distress and, less commonly, hypotonia. Symptoms were self limited and not associated with other neonatal conditions. When paroxetine was combined with clonazepam, infants with symptoms had significantly elevated paroxetine levels when compared with similarly exposed infants without symptoms (p <.05). Among single-agent paroxetine-exposed infants, drug levels did not differ significantly between those with and without symptoms. Maternal dose of clonazepam was significantly higher (p <.05) during pregnancy and at delivery among symptomatic infants compared with nonsymptomatic infants. Developmental outcomes at 2 and 8 months of age did not differ between symptomatic and nonsymptomatic infants. CONCLUSION: While transient neonatal symptoms were found in infants after single-agent prenatal exposure to SSRIs and when paroxetine was combined with clonazepam, the addition of clonazepam appeared to alter paroxetine metabolism, leading to increased drug levels and risk for transient neonatal symptoms. These data highlight the importance of accounting for a variety of pharmacologic factors beyond single-agent SSRI exposure that may lead to poor neonatal adaptation. Further studies are needed with a larger sample of infants to determine the role of clonazepam and whether similar outcomes occur when exposure includes other SSRIs in combination with clonazepam.

High levels of estradiol impair spatial performance in the Morris water maze and increase 'depressive-like' behaviors in the female meadow vole.

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more 'depressive-like' behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swam to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased 'depressive-like' behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that 'depressive-like' behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze.

Benefits and risks to mother and infant of drug treatment for postnatal depression.

The postnatal period presents a special problem to healthcare providers treating psychiatric disorders in women. Many new mothers who need antidepressant treatment may wish to breastfeed their infants, but are hesitant to do so for fear of passing on possible harmful effects of the medication through their milk. The focus of this article will be on highlighting and interpreting the existing literature on the benefits and risks to mother and infant of drug treatment for postnatal depression, as well as outlining treatment guidelines for the use of antidepressants in breastfeeding mothers. The article will specifically focus on the use of fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram, which are more commonly used and belong to the selective serotonin reuptake inhibitor group of antidepressants. The tricyclic and other newer antidepressant medications will also be discussed. As there are no published controlled studies on the use of antidepressants by breastfeeding women, publications of individual case reports, case series, and pharmacokinetic investigations serve as the basis for the development of treatment guidelines. Results from this growing body of literature are promising in that, with the exception of a few cases, no serious adverse events have been reported in infants exposed to antidepressant medications through breast milk. In addition nonpharmacological treatments consisting of different types of psychotherapies will be discussed. It is critical that healthcare providers evaluate each mother-infant dyad on an individual basis when faced with the decision to prescribe antidepressant medications during the postnatal period.