Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Systematic Review.

INTRODUCTION: Thymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors. METHODS: This systematic review was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies. RESULTS: A total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47-0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59-0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy. CONCLUSIONS: For patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.

Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Clinical Practice Guideline.

INTRODUCTION: The aim of this guideline was to provide recommendations for the most effective therapy for patients with thymic epithelial tumors, including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETs). This guideline is intended to be used by all health care professionals managing patients with thymic epithelial tumors. METHODS: The guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of the evidence, expert consensus, and formal internal and external reviews. RESULTS: Evidence-based recommendations were developed to improve the management of patients with thymic epithelial tumors. The guideline includes recommendations for surgical, radiation, and systemic treatments for patients with thymoma, thymic carcinoma, and thymic NETs separated by stage of disease using the TNM staging system. Recommendations for patients with thymic NETs were endorsed from the 2021 National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors Guideline. CONCLUSIONS: This guideline reflects the new staging system for patients with thymoma and thymic carcinoma and includes supporting evidence from the best available studies.

Clinical Practice Guidelines: Tools to Support High Quality Patient Care.

Clinical practice guidelines (CPGs) are systematically-developed statements aimed to assist decision-making relevant to the clinical encounter, to inform clinical policy, and to strengthen health care systems. The development of a CPG begins with the identification of a problem for which evidence-informed guidance is required. Interdisciplinary panels work to craft - and then execute - a protocol that will serve as a blueprint for the development process. It includes the scope of the project; who is involved and how they will function; the specific systematic review and consensus methods that will be used to ensure quality recommendations and to mitigate bias. CPGs should undergo a formal review of relevant stakeholders and results of this review, actions taken by the panel, and the final recommendations should be documented in the final CPG report. Dissemination activities, including the use of social media platforms, and more purposefully designed implementation activities are required to optimize the adoption of recommendations. Methods to keep recommendations current are required to ensure on-going validity and credibility of the recommendations. Two tools, AGREE II, and the AGREE REX, provide quality criteria related to the whole CPG development process and the CPG recommendations, respectively. The AGREE II is comprised of 23 items within 6 CPG quality domains: scope and purpose, stakeholder involvement, rigor, clarity of presentation, applicability, and editorial independence. The AGREE REX is comprised of 9 items within 3 CPG Recommendation quality domains: clinical applicability, values and preferences, and implementability. CPGs are important tools to an overall quality agenda.

Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review.

Second-line treatment options are limited for patients with advanced non-small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1-positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1-positive tumors).

Radiotherapy With Curative Intent in Patients With Early-stage, Medically Inoperable, Non-Small-cell Lung Cancer: A Systematic Review.

Patients with early-stage non-small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.

Colorectal Cancer Screening in Average Risk Populations: Evidence Summary.

Introduction. The objectives of this systematic review were to evaluate the evidence for different CRC screening tests and to determine the most appropriate ages of initiation and cessation for CRC screening and the most appropriate screening intervals for selected CRC screening tests in people at average risk for CRC. Methods. Electronic databases were searched for studies that addressed the research objectives. Meta-analyses were conducted with clinically homogenous trials. A working group reviewed the evidence to develop conclusions. Results. Thirty RCTs and 29 observational studies were included. Flexible sigmoidoscopy (FS) prevented CRC and led to the largest reduction in CRC mortality with a smaller but significant reduction in CRC mortality with the use of guaiac fecal occult blood tests (gFOBTs). There was insufficient or low quality evidence to support the use of other screening tests, including colonoscopy, as well as changing the ages of initiation and cessation for CRC screening with gFOBTs in Ontario. Either annual or biennial screening using gFOBT reduces CRC-related mortality. Conclusion. The evidentiary base supports the use of FS or FOBT (either annual or biennial) to screen patients at average risk for CRC. This work will guide the development of the provincial CRC screening program.

The Use of Systemic Treatment in the Maintenance of Patients with Non-Small Cell Lung Cancer: A Systematic Review.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression and potentially increase overall survival. Secondarily, it may increase the proportion of patients eligible for second-line therapy at the time of progression. The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for phase III randomized controlled trials comparing maintenance systemic treatment against another systemic treatment or placebo in patients with stage IIIB or IV NSCLC who had received a minimum of four prior cycles of platinum-based chemotherapy. Meta-analyses were conducted with clinically homogenous trials. RESULTS: Fourteen randomized controlled trials with 22 publications were included. The overall survival benefit was strongest for maintenance therapy with pemetrexed for patients with nonsquamous NSCLC (hazard ratio = 0.74, 95% confidence interval: 0.64-0.86) but not significant for patients with squamous NSCLC. There was also an overall survival benefit with maintenance therapy with epidermal growth factor receptor tyrosine kinase inhibitors, but the magnitude of the benefit was smaller than with pemetrexed (hazard ratio = 0.84, 95% confidence interval: 0.75-0.94). Docetaxel or gemcitabine as maintenance chemotherapies did not have an impact on overall survival. CONCLUSION: For patients with advanced, stable stage IIIB/IV NSCLC whose disease has not progressed after four to six cycles of platinum-based chemotherapy, the overall survival benefits were strongest for pemetrexed maintenance therapy followed by epidermal growth factor receptor tyrosine kinase inhibitor maintenance therapy.

Guideline for referral of patients with suspected prostate cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicion about the presence of prostate cancer in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network and from among the members of the Cancer Care Ontario Genitourinary Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of prostate cancer within the Canadian context. CONCLUSION: These guidelines might lead to more timely and appropriate referrals and might also be of value for informing the development of prostate cancer diagnostic programs and for helping policy makers to ensure appropriate resources are in place.

Systematic review of clinical features of suspected prostate cancer in primary care.

OBJECTIVE: To systematically review the literature and provide an update and integration of existing peer-reviewed guidelines with recent systematic reviews and with primary studies related to the early recognition and management of prostate cancer in primary care. DATA SOURCES: We searched MEDLINE and EMBASE for relevant articles. The quality of the evidence to support existing guideline recommendations and the consistency of recommendations with updated evidence were assessed. Applicability in a Canadian primary care setting was also evaluated. STUDY SELECTION: All studies conducted in the primary care setting that provided information on clinical features predictive of prostate cancer were included. Also, studies that assessed the accuracy of nomograms to predict prostate cancer were reviewed. SYNTHESIS: The findings suggest that lower urinary tract symptoms are not highly predictive of prostate cancer. However, evidence suggests that FPs might be good at discriminating between patients with and without prostate cancer using digital rectal examination and prostate-specific antigen testing. Nomograms might also be useful in assessing patients for aggressive prostate cancers. CONCLUSION: The results of this review can be used to inform recommendations for referral for suspected prostate cancer in the primary care setting. They could also inform development of prostate cancer diagnostic assessment programs.

Sentinel lymph node biopsy in vulvar cancer: Systematic review, meta-analysis and guideline recommendations.

OBJECTIVES: Traditionally, treatment for early stage vulvar cancer has included removal of the primary tumor and inguinofemoral lymph node dissection (IFLD). Sentinel lymph node biopsy (SLNB) has been proposed as an alternative to IFLD for early stage vulvar cancer patients. The aim of this project was to systematically review and assess the potential for harms and benefits with the SLNB procedure in order to make recommendations regarding the adoption of the procedure, selection of patients and appropriate technique and procedures. METHODS: A working group with expertise in gynecologic oncology and health research methodology was formed to lead the systematic review and process of guideline development. MEDLINE, Embase and The Cochrane Database of Systematic Reviews were searched for relevant articles published up to September 2014. Outcomes of interest included detection, false negative, complication and recurrence rates and indicators related to pathology. Meta-analyses were conducted where appropriate. RESULTS: The evidence-base of a previously published health technology assessment was adopted. An additional search to update the HTA's evidence base located three systematic reviews, and eleven individual studies that met the inclusion criteria. According to a meta-analysis, per groin detection rate for SLNB using radiocolloid tracer and blue dye was 87% [82-92]. The false negative rate with SLNB was 6.4% [4.4-8.8], and the recurrence rates with SLNB and IFLD were 2.8% [1.5-4.4] and 1.4% [0.5-2.6], respectively. An internal and external review process elicited concerns about the necessity of performing this procedure in an appropriate organizational context. CONCLUSION: SLNB is recommended for women with unifocal tumors<4 cm and clinically non-suspicious nodes in the groin, provided that specific infrastructure and human resource needs are met. Some recommendations for appropriate techniques and procedures are also provided.

Guideline for referral of patients with suspected lung cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicions about the presence of lung cancer in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network and from among the members of the Cancer Care Ontario Lung Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of lung cancer within the Canadian context. CONCLUSION: Earlier identification and referral of patients with lung cancer might ultimately help improve lung cancer morbidity and mortality. These guidelines might also be of value for informing the development of lung cancer diagnostic programs and for helping policy makers to ensure appropriate resources are in place.

Guideline for referral of patients with suspected colorectal cancer by family physicians and other primary care providers.

OBJECTIVE: The aim of this guideline is to assist FPs and other primary care providers with recognizing features that should raise their suspicions about the presence of colorectal cancer (CRC) in their patients. COMPOSITION OF THE COMMITTEE: Committee members were selected from among the regional primary care leads from the Cancer Care Ontario Provincial Primary Care and Cancer Network, the members of the Ontario Colorectal Cancer Screening Advisory Committee, and the members of the Cancer Care Ontario Gastrointestinal Cancer Disease Site Group. METHODS: This guideline was developed through systematic review of the evidence base, synthesis of the evidence, and formal external review involving Canadian stakeholders to validate the relevance of recommendations. REPORT: Evidence-based guidelines were developed to improve the management of patients presenting with clinical features of CRC within the Canadian context. CONCLUSION: The judicious balancing of suspicion of CRC and level of risk of CRC should encourage timely referral by FPs and primary care providers. This guideline might also inform indications for referral to CRC diagnostic assessment programs.

Systematic review of guidelines for the management of suspected lung cancer in primary care.

OBJECTIVE: To systematically review the literature and provide an update and integration of existing peer-reviewed guidelines with recent systematic reviews and with primary studies related to the early recognition and management of lung cancer in primary care. DATA SOURCES: MEDLINE and EMBASE were searched for relevant articles. The quality of the evidence to support existing guideline recommendations, and the consistency of recommendations with updated evidence, were assessed. Applicability in a Canadian primary care setting was also evaluated. STUDY SELECTION: All studies that explored signs or symptoms of or risk factors for lung cancer in the primary care setting were included. All diagnostic studies in which symptomatic primary care patients underwent 1 or more investigations were also searched. SYNTHESIS: Recommendations were consistent among guidelines despite a paucity of supporting evidence. Updated evidence provided further support for the recommendations. Recommendations for identifying signs and symptoms of lung cancer presenting in primary care and for initial management can be adopted and applied within a Canadian primary care setting. CONCLUSION: This updated review of recommendations might help promote evidence-based practice and, ultimately, more timely management and improved prognosis for lung cancer patients. It might also assist in the development of lung cancer diagnostic assessment programs.

Systematic review of clinical features of suspected colorectal cancer in primary care.

OBJECTIVE: To systematically review the diagnostic accuracy of clinical features associated with colorectal cancer (CRC) presenting in primary care. DATA SOURCES: MEDLINE and EMBASE were searched for studies in primary care that provided information on clinical features predictive of CRC. Positive predictive values were used to guide the determination of clinical features associated with increased risk of CRC. STUDY SELECTION: Systematic reviews or primary studies that provided possible clinical features predictive of CRC were included. SYNTHESIS: Clinical features of patients presenting in primary care that are associated with increased risk of CRC, listed in descending order of association, included palpable rectal or abdominal mass; rectal bleeding combined with weight loss; iron deficiency anemia; rectal bleeding mixed with stool; rectal bleeding in the absence of perianal symptoms; rectal bleeding combined with change in bowel habits; dark rectal bleeding; rectal bleeding and diarrhea; and change in bowel habits. Being male and increasing age were also, in general, associated with increased risk of CRC. CONCLUSION: Recognition of clinical features associated with increased risk of CRC by FPs might help with earlier identification and referral among patients presenting in primary care. This review might help inform providers and CRC diagnostic assessment programs about indications for assessment and further investigation.

Systematic review on hormone receptor testing in breast cancer.

Assessment of hormone receptors (estrogen and progesterone) helps to direct therapy for women with breast cancer. Immunohistochemistry is most commonly used to assess hormone receptor status and it is essential that these tests are performed accurately and reliably within and across laboratories. The overall purpose of this guideline is to improve the quality and accuracy of hormone receptor testing and its utility as a prognostic and predictive marker for invasive and in situ breast cancer. Medline, EMBASE, the Cochrane Database of Systematic Reviews, and abstracts from the San Antonio Breast Cancer Symposium were searched. An environmental scan of the internet and of international guideline developers and key organizations was performed. Preanalytic elements such as the collection, fixation, and storage of samples, and analytic elements such as selection of antibodies and scoring methods that seem to offer the best results for immunohistochemical assessment of hormone receptors are presented. Proficiency testing or quality assurance of immunohistochemistry is described.

Anthropometry and body composition do not predict bioavailable androgen or progesterone concentration in adolescent girls.

Our objective was to test the hypothesis that anthropometry and body composition were independently associated with sex-steroid concentration in adolescent girls. Premenarcheal (age, mean +/- SD = 10.9 +/- 0.6, N = 51), perimenarcheal (age = 13.7 +/- 0.6, N = 74), and postmenarcheal (age = 16.7 +/- 0.6, N = 44) cohorts provided saliva at morning recess during the schoolday over 6 weeks. Estradiol, testosterone, progesterone, and dehydroepiandrosterone (DHEA) were quantified. Age, developmental cohort, self-reported Tanner stage of breast development and pubic-hair distribution, gynecological age, height, weight, waist/hip ratio, and percent body fat (by impedance) were assessed. Repeated measures were reduced to a mean. Data were hierarchically standardized for sexual maturation status, and then used to predict anthropometry/percent body fat. After intensive repeated sampling, individuals still varied widely in testosterone, progesterone, and DHEA concentrations within a developmental cohort (35.0 < or = coefficient of variation < or = 66.5%). Individual hormone concentration was repeatable across 2 years (0.51 < or = r(2) < or = 0.73). In spite of the variability within a cohort, there was no evidence for an association between the standardized hormone and body mass index, percent body fat, or waist/hip ratio, whether or not measures were age-adjusted (21 univariate tests; 0.19 < or = P < or = 0.96). Stratification by developmental cohort also did not reveal associations. Low estradiol assay precision precluded analyses. In conclusion, despite considerable population variation in hormone concentration after repeated sampling, no evidence supported an association between anthropometry or pecent body fat and testosterone, progesterone, or DHEA in adolescent girls.

Ontogeny of the transition from killer to caregiver in dwarf hamsters (Phodopus campbelli) with biparental care.

Biparental Phodopus campbelli and uniparental P. sungorus juvenile litters (2 males, 2 females) both consumed amniotic fluid and placenta during the birth of younger siblings. Three days later, P. campbelli juveniles were most responsive to a displaced younger sibling. Thus, P. campbelli are responsive to pups as juvenile alloparents and as new parents; however, at intervening ages, infanticidal attack (bite) was seen. At 5, 7, 9, 11, or 13 weeks of age, male and female P. campbelli were given a 5-min test with an unrelated, 3-day-old, anesthetized pup. Females attacked more often than males, yet pup-retrieval rates did not differ. Female aggression increased with age and was replaced by retrieval behavior 3 days after parturition. Male attack ceased after a birth, but parental behavior did not increase, remaining below the rate for new fathers tested with their own awake pup. Over repeated testing, behavior in one test did not predict behavior in another. Transitions from caregiving alloparent to infanticidal adult and back to parental care were clear in females, but less discrete with this stimulus paradigm in these highly paternal males.

Dopamine agonist treatment before and after the birth reduces prolactin concentration but does not impair paternal responsiveness in Djungarian hamsters, Phodopus campbelli.

Male Djungarian hamsters, Phodopus campbelli, are highly parental and experience a late-afternoon prolactin surge before the birth that is not seen in a closely related species, P. sungorus, which lacks paternal care. At the same stage, female prolactin is needed for later maternal behavior. Male prolactin was suppressed in first-time fathers before the birth of the litter using two different dopamine agonists, bromocriptine mesylate and cabergoline. Plasma prolactin concentration confirmed the efficacy of each treatment. Paternal responsiveness was quantified using three variations on a pup-displacement paradigm. No adverse effects of either treatment were seen. Across four experiments, there was no decrease in paternal retrieval or in retrieval latency in response to male prolactin suppression. In addition, there was no decrease in litter growth or survival, nor was there an increase in maternal investment to compensate for a deficit in paternal care. As cabergoline suppression of prolactin persisted after the birth without behavioral deficits, prolactin after the birth was also not required for the expression of paternal behavior. In spite of an extensive literature supporting an association between prolactin and natural paternal behavior, we conclude that dopamine-mediated prolactin release into peripheral plasma is not essential for paternal responsiveness in P. campbelli.

Neonatal anesthesia for studies of hamster parental behavior when infanticidal aggression is a possibility.

Experiments involving investigation of the neuroendocrine basis for paternal care in rodents risk activation of aggressive behavior toward pups. To minimize pain and suffering during tests of parental responsiveness requiring retrieval of a displaced pup to its nest, a method of anesthetizing the pup was developed in Djungarian hamsters, Phodopus campbelli. A surgical plane of anesthesia, as measured by criteria, such as respiratory depression, loss of the pedal reflex, and failure to increase respiratory rate or to vocalize in response to handling, was achieved by use of intraperitoneal administration of a combination of ketamine and xylazine. Both parents (tested separately) expressed normal behavior toward anesthetized pups. In random order, a saline-injected or anesthetized pup was displaced from its nest in the home cage. There were no differences in pick-up or retrieval rates between saline and anesthetized pups for either parent. A third test using an unmanipulated pup confirmed that parental behavior was not reduced toward an anesthetized pup. However, if anesthetized pups were tested first among littermates, retrieval by males was less likely. This method will, therefore, underestimate retrieval behavior in males, but not females. Adult male hamsters that had never been parents also expressed expected behavior by attacking the pup in 45% of cases. This method provides an efficient and effective means of protecting pups while allowing adults to express a wide range of parental and infanticidal behaviors. It also has application in behavioral screening of transgenic strains toward unrelated young.