Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas

The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers

Phantom-based quality assurance for multicenter quantitative MRI in locally advanced cervical cancer

Background and purpose: A wide variation of MRI systems is a challenge in multicenter imaging biomarker studies as it adds variation in quantitative MRI values. The aim of this study was to design and test a quality assurance (QA) framework based on phantom measurements, for the quantitative MRI protocols of a multicenter imaging biomarker trial of locally advanced cervical cancer. Materials and methods: Fifteen institutes participated (five 1.5 T and ten 3 T scanners). Each institute optimized protocols for T2, diffusion-weighted imaging, T1, and dynamic contrast-enhanced (DCE–)MRI according to system possibilities, institutional preferences and study-specific constraints. Calibration phantoms with known values were used for validation. Benchmark protocols, similar on all systems, were used to investigate whether differences resulted from variations in institutional protocols or from system variations. Bias, repeatability (%RC), and reproducibility (%RDC) were determined. Ratios were used for T2 and T1 values. Results: The institutional protocols showed a range in bias of 0.88–0.98 for T2 (median %RC = 1%; %RDC = 12%), −0.007 to 0.029 × 10−3 mm2/s for the apparent diffusion coefficient (median %RC = 3%; %RDC = 18%), and 0.39–1.29 for T1 (median %RC = 1%; %RDC = 33%). For DCE a nonlinear vendor-specific relation was observed between measured and true concentrations with magnitude data, whereas the relation was linear when phase data was used. Conclusion: We designed a QA framework for quantitative MRI protocols and demonstrated for a multicenter trial for cervical cancer that measurement of consistent T2 and apparent diffusion coefficient values is feasible despite protocol differences. For DCE–MRI and T1 mapping with the variable flip angle method, this was more challenging

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m 2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m 2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population

Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study.

Purpose BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives. Methods We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs). Results A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort. Conclusion Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives. Genetics in Medicine advance online publication, 22 March 2018; doi:10.1038/gim.2018.44

Association of persistent morbidity after radiotherapy with quality of life in locally advanced cervical cancer survivors

PURPOSE: To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors. MATERIAL AND METHODS: Longitudinal outcome from the EMBRACE-I study was evaluated. Patient-reported symptoms and QOL were prospectively scored (EORTC-C30/CX24) at baseline and regular follow-ups. Physician-assessed symptoms were also reported (CTCAEv.3). Persistent symptoms were defined if present in at least half of the follow-ups. QOL items were linearly transformed into a continuous scale. Linear mixed-effects models (LMM) were applied to evaluate and quantify the association of persistent symptoms with QOL. Overall QOL deterioration was evaluated by calculating the integral difference in QOL over time obtained with LMM for patients without and with persistent symptoms. RESULTS: Out of 1416 patients enrolled, 741 with baseline and ≥ 3 late follow-ups were analyzed (median 59 months). Proportions of persistent EORTC symptoms ranged from 21.8 % to 64.9 % (bowel control and tiredness). For CTCAE the range was 11.3-28.6 % (limb edema and fatigue). Presence of any persistent symptom was associated with QOL, although with varying magnitude. Role functioning and Global health/QOL were the most impaired aspects. Fatigue and pain showed large differences, with reductions of around 20 % for most of the QOL aspects. Among organ-related symptoms, abdominal cramps showed the largest effect. CONCLUSION: Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management

Challenges in Preloss Care to Parents Facing Their Child's End-of-Life: A Qualitative Study From the Clinicians Perspective

Objective: Bereavement care for parents predominantly focuses on care after child loss. However, Health Care Professionals (HCPs) feel responsible for supporting parents who are grieving losses in their child's end-of-life. Preloss care is tailored to the parents’ needs, thus highly varying. To better understand the nature of preloss care, this study aims to gain insight into the challenges HCPs encounter while providing care for parents during their child's end-of-life. Methods: Exploratory qualitative research using semistructured interviews with physicians and nurses working in neonatology and pediatrics in 3 university pediatric hospitals and 1 child home care service. A multidisciplinary team thematically analyzed the data. Results: Twenty-two HCPs participated in this study. From the HCPs' inner perspective, three dyadic dimensions in preloss care delivery were identified that create tension in HCPs: sustaining hope versus realistic prospects, obtaining emotional closeness versus emotional distance, and exploring emotions versus containing emotions. Throughout preloss care delivery, HCPs weighed which strategies to use based on their perception of parental needs, the situation, and their own competencies. HCPs remained with lingering uncertainties on whether the preloss care they provide constituted optimal care. Conclusions: As a result of the experienced tension, HCPs are at risk for prolonged distress and possibly even compassion fatigue. In order to maintain a positive emotional balance in HCPs, education should focus on adapting positive coping strategies and provide hands-on training. Furthermore, on an institutional level a safe environment should be fostered and well-being could be enhanced through learning by sharing as a team

A grounded theory study on the dynamics of parental grief during the children's end of life

AIM: Parents are increasingly confronted with loss during their child's end of life. Healthcare professionals struggle with parental responses to loss. This study aimed to understand parental coping with grief during their child's end of life. METHODS: A grounded theory study was performed, using semi-structured interviews with parents during the child's end of life and recently bereaved parents. Data were collected in four children's university hospitals and paediatric homecare services between October 2020 and December 2021. A multidisciplinary team conducted the analysis. RESULTS: In total, 38 parents of 22 children participated. Parents strived to sustain family life, to be a good parent and to ensure a full life for their child. Meanwhile parents' grief increased because of their hypervigilance towards signs of loss. Parents' coping with grief is characterised by an interplay of downregulating grief and connecting with grief, aimed at creating emotional space to be present and connect with their child. Parents connected with grief when it was forced upon them or when they momentarily allowed themselves to. CONCLUSION: The parents' ability to engage with grief becomes strained during the end of life. Healthcare professionals should support parents in their search for a balance that facilitates creating emotional space

Health care professionals' experiences with pre-loss care in pediatrics; goals, strategies, obstacles and facilitators

Context: Although parents experience grief when confronted with their child's deterioration and imminent death, most bereavement care is focused on supporting parents after child loss. Insight into intentions and strategies of the health care professionals (HCPs) in preloss care during the end of life is still lacking. Objectives: To create a starting point for improvement of preloss care, this study explores HCPs' experiences with providing support aimed at parental feelings of grief during the child's end of life. Methods: Exploratory qualitative research using individual semistructured interviews with clinicians in pediatrics and neonatology in hospital and homecare settings. Data were thematically analyzed by a multidisciplinary team. Results: Nineteen HCPs participated. HCPs tried to ensure that parents could reflect on the care received as concordant to their preferences and were not hindered in their bereavement as a consequence of their professional actions. Strategies included maximizing parental presence, enabling parental involvement in decision making, and ensuring a dignified death. While using these strategies, HCPs faced several difficulties: uncertainty about the illness course, unpredictability of parental grief responses, and being affected themselves by the child's imminent death. It helped HCPs to develop a bond with parents, find comfort with colleagues, and making joint decisions with colleagues. Conclusion: HCPs strive to improve parental coping after the child's death, yet apply strategies that positively influence parental preparedness and well-being during the end of life as well. Individual HCPs are left with many uncertainties. A more robust approach based on theory, evidence, and training is needed to improve preloss care in pediatrics

Risk factors for nodal failure after radiochemotherapy and image-guided brachytherapy in locally advanced cervical cancer: an EMBRACE analysis

OBJECTIVE: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. MATERIALS AND METHODS: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). RESULTS: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28-1.00, p=0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17-0.86, p=0.02). For subgroup 2 only local failure was associated with higher risk of NF. CONCLUSION: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis