Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

Factors Associated with Late Local Radiation Toxicity after Post-Operative Breast Irradiation.

Purpose: To assess determinants associated with late local radiation toxicity in patients treated for breast cancer. Methods: A systematic review was performed. All studies reporting ≥2 variables associated with late local radiation toxicity after treatment with postoperative whole breast irradiation were included. Cohort studies, randomized controlled trials, and cross-sectional studies were eligible designs. Study characteristics and definitions of determinants and outcome measures were extracted. If possible, the measure of association was extracted. Results: Twenty-one studies were included in this review. Six out of seven studies focused on the association between radiotherapy (boost) dose or irradiated breast volume and late radiation toxicity found significant results. Tumor bed boost was associated with late radiation toxicity, fibrosis, and/or edema in six out of twelve studies. Lower age was associated with late breast toxicity in one study, while in another study, higher age was significantly associated with breast fibrosis. Also, no association between age and late radiation toxicity was found in eight out of twelve studies. Similar inconsistent results were found in the association between late radiation toxicity and other patient-related factors (i.e., breast size, diabetes mellitus) and surgical and systemic treatment-related factors (i.e., complications after surgery, chemotherapy, and time between surgery and radiotherapy). Conclusion: In modern 3D radiotherapy, radiotherapy (boost) dose and volume are-like in 2D radiotherapy-associated with late local radiation toxicity, such as breast fibrosis and edema. Treatment de-escalation, for example, partial breast irradiation in selected patients might be important to decrease late local toxicity without compromising locoregional control and survival.

Patient-reported cosmetic satisfaction and the long-term association with quality of life in irradiated breast cancer patients.

PURPOSE: To evaluate patient-reported cosmetic satisfaction in women treated with radiation therapy for breast cancer and to determine the association between dissatisfaction and quality of life (QoL) and depression. METHODS: Within the prospective UMBRELLA breast cancer cohort, all patients ≥ 1 year after breast conserving treatment or mastectomy with immediate reconstruction were selected. Self-reported cosmetic satisfaction was measured on a 5-point Likert scale. QoL, social functioning, and emotional functioning were measured using EORTC QLQ-C30 and BR23 at 1, 2, and 3 years after inclusion. Mixed model analysis was performed to assess the difference in different domains of QoL between patients with good versus poor self-reported cosmetic satisfaction over time after adjustment for potential confounders. Depression scores were collected by means of the HADS-NL questionnaire. Chi-square test or Fisher's exact test was used to assess the difference in proportions of HADS score ≥ 8, indicating increased depression risk, between satisfied and dissatisfied patients. RESULTS: 808 patients were selected for analysis. Respectively one, two, and three years after surgery, 8% (63/808), 7% (45/626), and 8% (31/409) of patients were dissatisfied with their cosmetic outcome. Poor patient-reported cosmetic satisfaction was independently associated with impaired QoL, body image, and lower emotional and social functioning. Scores ≥ 8 on the HADS depression subscale were significantly more common in dissatisfied patients. CONCLUSIONS: Dissatisfaction with cosmetic outcome was low after breast cancer surgery followed by radiation therapy during 3 years follow-up. Knowing the association between dissatisfaction with cosmetic outcome and QoL and depression could help to improve the preoperative counseling of breast cancer patients.

Pathological Complete Response Following Different Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Pathological complete response (pCR) following neoadjuvant treatment for locally advanced rectal cancer (LARC) is associated with better survival, less local recurrence, and less distant failure. Furthermore, pCR indicates that the rectum may have been preserved. This meta-analysis gives an overview of available neoadjuvant treatment strategies for LARC and analyzes how these perform in achieving pCR as compared with the standard of care. METHODS: Pubmed, Embase, and Cochrane Central bibliographic databases were searched. Randomized controlled trials in which patients received neoadjuvant treatment for MRI-staged nonmetastatic resectable LARC were included. The primary outcome was pCR, defined as ypT0N0. A meta-analysis of studies comparing an intervention with standard fluoropyrimidine-based chemoradiation (CRT) was performed. RESULTS: Of the 17 articles included in the systematic review, 11 were used for the meta-analysis. Addition of oxaliplatin to fluoropyrimidine-based CRT resulted in significantly more pCR compared with fluoropyrimidine-based CRT only (OR 1.46), but at the expense of more ≥ grade 3 toxicity. Other treatment strategies, including consolidation/induction chemotherapy and short-course radiotherapy (SCRT), did not improve pCR rates. None of the included trials reported a benefit in local control or OS. Five-year DFS was significantly worse after SCRT-delay compared with CRT (59% vs. 75.1%, HR 1.93). CONCLUSIONS: All included trials fail to deliver high-level evidence to show an improvement in pCR compared with standard fluoropyrimidine-based CRT. The addition of oxaliplatin might result in more pCR but at the expense of more toxicity. Furthermore, this benefit does not translate into less local recurrence or improved survival.

Surgery for multiple endocrine neoplasia type 1-related insulinoma: long-term outcomes in a large international cohort.

BACKGROUND: Insulinomas are found in 10-15 per cent of patients with multiple endocrine neoplasia type 1 (MEN1) and lead to life-threatening hypoglycaemia. Surgical outcome and the optimal surgical strategy for MEN1-related insulinoma are unknown. METHODS: Patients with MEN1-related insulinomas were identified in 46 centres in Europe and North America between 1990 and 2016. Insulinomas were considered localized if the lesion was in the pancreatic head or body/tail. Patients with pancreatic neuroendocrine tumours throughout the pancreas were suspected of having multifocal insulinoma. The primary outcome was postoperative hypoglycaemia, defined as persistent hypoglycaemia, or recurrent hypoglycaemia caused by a new insulinoma or insulin-producing liver metastases. Hypoglycaemia-free survival was estimated by the Kaplan-Meier method. RESULTS: Ninety-six patients underwent resection for MEN1-related insulinoma. Sixty-three and 33 patients had localized and multifocal insulinomas respectively. After a median follow-up of 8 (range 1-22) years, one patient (1 per cent) had persistent disease and six (6 per cent) had developed recurrent disease, of whom four had a new insulinoma. The 10-year hypoglycaemia-free survival rate was 91 (95 per cent c.i. 80 to 96) per cent. Of those with localized disease, 46 patients underwent pancreatic resection and 17 enucleation. One of these patients had persistent disease and one developed recurrent insulinoma. Among patients with multifocal disease, three developed new insulinomas and two developed insulin-producing liver metastases. CONCLUSION: Surgery for MEN1-related insulinoma is more successful than previously thought.

ANTECEDENTES: Del 10% al 15% de los pacientes con MEN1 presentan insulinomas que pueden desencadenar una hipoglucemia potencialmente mortal. Se desconoce el resultado de la cirugía y la estrategia quirúrgica óptima para el tratamiento del insulinoma relacionado con el MEN1. MÉTODOS: Se identificaron los pacientes con insulinomas relacionados con el MEN1 en 46 centros de Europa y América del Norte entre 1990 y 2016. Los insulinomas se consideraron localizados si el tumor se localizaba en la cabeza o en el cuerpo/cola del páncreas. Se sospechó la existencia de un insulinoma multifocal en los pacientes con tumores neuroendocrinos pancreáticos (pNETs). El objetivo primario de este estudio fue evaluar la hipoglucemia postoperatoria, definida como hipoglucemia persistente, hipoglucemia recidivante causada por un nuevo insulinoma o debida a metástasis hepáticas productoras de insulina. La supervivencia libre de hipoglucemia se estimó mediante el método de Kaplan-Meier. RESULTADOS: A 96 se les realizó una resección por insulinoma en el contexto del MEN1. Un total de 63 y 33 pacientes presentaron insulinomas localizados y multifocales, respectivamente. Después de una mediana de seguimiento de 7,8 años (rango 1-22), un paciente (1%) tenía enfermedad persistente y seis pacientes (6%) presentaron enfermedad recidivante, de los cuales cuatro desarrollaron un nuevo insulinoma. La supervivencia libre de hipoglucemia fue del 91% a los 10 años (i.c. del 95%, 80%-96%). De los pacientes con enfermedad localizada, 46 fueron sometidos a resección pancreática y 17 pacientes a enucleación. Entre éstos, un paciente tenía enfermedad persistente y uno desarrolló insulinoma recidivante, respectivamente. De los pacientes con enfermedad multifocal, tres desarrollaron nuevos insulinomas y dos desarrollaron metástasis hepáticas productoras de insulina. CONCLUSIÓN: La cirugía para el insulinoma en el contexto del MEN1 es más exitosa de lo que parecía en principio.

Pre-treatment expectations of patients with spinal metastases: what do we know and what can we learn from other disciplines? A systematic review of qualitative studies.

BACKGROUND: Little is known about treatment expectations of patients with spinal metastases undergoing radiotherapy and/or surgery. Assuming that patients with spinal metastases share characteristics with patients who had spinal surgery for non-cancer related conditions and with advanced cancer patients, we performed a systematic review to summarize the literature on patient expectations regarding treatment outcomes of spinal surgery and advanced cancer care. METHODS: A comprehensive search was performed in MEDLINE, EMBASE and PsycINFO for studies between 2000 and sep-2019. Studies including adult patients (> 18 years), undergoing spinal surgery or receiving advanced cancer care, investigating patients' pre-treatment expectations regarding treatment outcomes were included. Two independent reviewers screened titles, abstracts and full-texts, extracted data and assessed methodological quality. RESULTS: The search identified 7343 articles, of which 92 were selected for full-text review. For this review, 31 articles were included. Patients undergoing spinal surgery had overly optimistic expectations regarding pain and symptom relief, they underestimated the probability of functional disability, and overestimated the probability of (complete) recovery and return to work. Studies highlighted that patients feel not adequately prepared for surgery in terms of post-treatment expectations. Similarly, advanced cancer patients receiving palliative treatment often had overly optimistic expectations regarding their survival probability and cure rates. CONCLUSIONS: Patients tend to have overly optimistic expectations regarding pain and symptom relief, recovery and prognosis following spinal surgery or advanced cancer care. Pretreatment consultation about the expected pain and symptom relief, recovery and prognosis may improve understanding of prognosis, and promote and manage expectations, which, in turn, may lead to better perceived outcomes. TRIAL REGISTRATION: PROSPERO registration number: CRD42020145151 .

Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE): study protocol for a trial within a cohort study.

BACKGROUND: Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. METHODS/DESIGN: MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. DISCUSSION: The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. TRIAL REGISTRATION: Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281.

Impact of body fat distribution and sarcopenia on the overall survival in patients with spinal metastases receiving radiotherapy treatment: a prospective cohort study.

Introduction: An increasing number of patients is diagnosed with spinal metastases due to elevated cancer incidence and improved overall survival. Patients with symptomatic spinal bone metastases often receive radiotherapy with or without surgical stabilisation. Patients with a life expectancy of less than 3 months are generally deemed unfit for surgery, therefore adequate pre-treatment assessment of life expectancy is necessary. The aim of this study was to assess new factors associated with overall survival for this category of patients.Patients and methods: Patients who received radiotherapy for thoracic or lumbar spinal metastases from June 2013 to December 2016 were included in this study. The pre-treatment planning CT for radiotherapy treatment was used to assess the patient's visceral fat area, subcutaneous fat area, total muscle area and skeletal muscle density on a single transverse slice at the L3 level. The total muscle area was used to assess sarcopenia. Furthermore, data were collected on age, sex, primary tumour, Karnofsky performance score, medical history, number of bone metastases, non-bone metastases and neurological symptoms. Univariable and multivariable cox regressions were performed to determine the association between our variables of interest and the survival at 90 and 365 days.Results: A total of 310 patients was included. The median age was 67 years. Overall survival rates for 90 and 365 days were 71% and 36% respectively. For 90- and 365-day survival, the Karnofsky performance score, muscle density and primary tumour were independently significantly associated. The visceral or subcutaneous fat area and their ratio and sarcopenia were not independently associated with overall survival.Conclusions: Of the body morphology, only muscle density was statistically significant associated with overall survival after 90 and 365 days in patients with spinal bone metastases. Body fat distribution was not significantly associated with overall survival.

The effect of chemotherapy on subjective cognitive function in younger early-stage breast cancer survivors treated with chemotherapy compared to older patients.

PURPOSE: To evaluate the impact of chemotherapy on subjective cognitive functioning according to age in a large cohort of breast cancer patients. METHODS: Within the UMBRELLA cohort, 715 patients with early-stage primary invasive breast cancer (T1-3N0-1M0) were selected. Subjective cognitive function was assessed by means of the EORTC QLQ-C30 up to 24 months and compared between patients treated with and without chemotherapy, for three different age strata (355 patients < 55 years, 240 patients aged 55-65 years, and 120 patients > 65 years). Differences between chemotherapy and non-chemotherapy patients by age at different time points were assessed by linear mixed-effect models correcting for age, tumor stage, educational level, endocrine therapy, anxiety, and depression. RESULTS: In total, 979 patients from the UMBRELLA cohort were included, of which 715 (73%) responded to baseline and at least one follow-up questionnaire. Questionnaire response rates ranged between 92 and 70%. The proportion of patients treated with chemotherapy decreased with age: 64% (n = 277) in patients < 55 years, 45% (n = 107) in patients 55-65 years, and 23% (n = 27) in patients > 65 years. Chemotherapy was associated with reduced subjective cognitive functioning. The impact of chemotherapy on subjective cognitive function was most pronounced in patients < 55 years, followed by those between 55 and 65 years. In the youngest age groups, patients treated with chemotherapy had significantly lower cognitive functioning up to 24 months. In women over 65 years, subjective cognitive functioning was comparable between patients treated with and without chemotherapy. CONCLUSION: This study confirms that chemotherapy is associated with impaired subjective self-reported cognitive functioning in breast cancer patients, and the effect persists at least up to 2 years after diagnosis. The impact of chemotherapy on self-reported cognitive functioning in the first 24 months is most pronounced in younger patients, especially those under 55 years of age.

Sparing the surgical area with stereotactic body radiotherapy for combined treatment of spinal metastases: a treatment planning study.

INTRODUCTION: Decreasing the radiation dose in the surgical area is important to lower the risk of wound complications when surgery and radiotherapy are combined for the treatment of spinal metastases. The purpose of this study was to compare the radiation dose in the surgical area for spinal metastases between single fraction external beam radiotherapy (EBRT), single fraction stereotactic body radiotherapy (SBRT) and single fraction SBRT with active sparing (SBRT-AS) of the posterior surgical area. METHODS: Radiotherapy treatment plans for EBRT, SBRT and SBRT-AS of the posterior surgical area were created for 13 patients with spinal metastases. A single fraction of 8Gy was prescribed to the spinal metastasis in the EBRT plan. For the SBRT treatment plans, a single fraction of 18Gy was prescribed to the metastasis and 8Gy to the rest of the vertebral body. For the SBRT plan with active sparing the dose in the designated surgical area was minimized without compromising the dose to the organs at risk. RESULTS: The median dose in the surgical area was 2.6Gy (1.6-5.3Gy) in the SBRT plan with active sparing of the surgical area compared to a median dose of 3.7Gy (1.6-6.3Gy) in the SBRT plan without sparing and 6.5Gy (3.5-9.1Gy) in the EBRT plans (p < .001). The radiation doses to the spinal metastases and organs at risk were not significantly different between the SBRT plan with and without sparing the surgical area. CONCLUSIONS: The radiation dose to the surgical area is significantly decreased with the use of SBRT compared to EBRT. Active sparing of the surgical area further decreased the mean radiation dose in the surgical area without compromising the dose to the spinal metastasis and the organs at risk.

Physical activity levels of women with breast cancer during and after treatment, a comparison with the Dutch female population.

Background: Physical activity has been shown to reduce side-effects of breast cancer and its treatment. As physical activity levels of patients with breast cancer are largely unknown, we investigated these levels and compared them to women from the general population. Methods: In this prospective cohort study, physical activity levels of women with breast cancer participating in the UMBRELLA cohort were assessed at radiotherapy intake and thereafter every 6 months up to 3 years with the SQUASH questionnaire, which was also used in a random sample of the Dutch population. We compared physical activity levels (no activity, low, moderate or high levels of sports, leisure time or total activity) between patients and the Dutch female population using multinomial logistic regression. Standardized Prevalence Ratios (SPR) were calculated to compare adherence to Dutch physical activity guidelines. Results: Women with breast cancer (nbaseline = 1655, n6 months = 1414, n12 months = 1186, n18 months = 957, n24 months = 744, n30 months = 555, and n36 months = 377) were less likely to spend time in physical activity compared to the general population (n = 11,710) until 3 years post-diagnosis, especially after 6 months (ORhigh-vs.-no activity = 0.34, 95% CI: 0.28-0.41). From 12 months onwards, patients were more likely to perform sports compared to the general population, especially patients who underwent systemic therapy. Guideline adherence was significantly lower in patients at baseline and 6 months (SPRbaseline = 89, 95% CI: 82-97; SPR6 months = 88, 95% CI: 81-96), and comparable to the general population at 12-36 months, especially in older women. Conclusions: Physical activity levels in women with breast cancer during and after treatment were lower compared to the Dutch female population. Three years post-treatment, they were still less physically active, although they spend more time in sport activities. As about half of the patients did not perform any sports, physical activity needs to be stimulated during and after treatment.

Severe depression more common in patients with ductal carcinoma in situ than early-stage invasive breast cancer patients.

PURPOSE: Ductal carcinoma in situ (DCIS) is associated with an excellent prognosis; historical studies have shown similar levels of psychological distress in patients with DCIS and with early-stage invasive breast cancer (early-IBC). It is suggested that these results might have led to better patient education about prognosis after DCIS. This study reports the current levels of anxiety, depression, and health-related quality of life (HRQoL) in DCIS and early-IBC patients. METHODS: DCIS (n = 89) and early-IBC patients, T1-2N0, (n = 361) were selected from the UMBRELLA breast cancer cohort. Patient-reported outcomes were prospectively collected before the start of adjuvant radiotherapy (baseline) and at 3, 6, 12, 18, and 24 months thereafter. Mixed models were used to compare differences in levels of anxiety, depression, and HRQoL between DCIS and early-IBC patients. RESULTS: DCIS and early-IBC patients reported similar levels of anxiety, which were highest at baseline. Depression scores were comparable between groups, also after stratification by use of adjuvant chemotherapy. The proportion of patients reporting high-risk depression scores (i.e., Hospital Anxiety and Depression Sale score >8) was significantly higher among patients with DCIS at 6, 12 and 18 months, and this proportion increased over the first 18 months. Health-related quality of life was comparable between both groups. CONCLUSION: Severe depression scores are more common in DCIS patients, despite their excellent prognosis. These results suggest that further improvement of patient education and effective patient doctor communication about the prognostic differences between patients with DCIS and invasive breast cancer is still highly needed.

The Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA): objectives, design, and baseline results.

PURPOSE: In oncology, RCTs are often beset by slow recruitment, limited generalizability, and strong preferences for interventions by patients and physicians. The cohort multiple randomized controlled trial (cmRCT) is an innovative design with the potential to overcome those challenges. In cmRCT, a prospective cohort serves as an infrastructure for multiple RCTs. We implemented cmRCT in a clinical breast cancer setting by creating UMBRELLA-a large prospective cohort of breast cancer and DCIS patients/survivors. METHODS: For all participants, clinical data and patient-reported outcomes (PROs, i.e., quality of life, fatigue, anxiety and depression, physical activity, work ability, and cosmetic satisfaction) are being collected at regular time-intervals for a period of 10 years. These data are being used both for observational and randomized studies. For each intervention to be tested against standard care, a subcohort of eligible patients is identified within UMBRELLA. From this subcohort, a random sample of patients is offered the intervention. Their outcomes are compared to the outcomes of patients receiving standard care. RESULTS: So far, between October 2013 and July 2016, we have recruited 1308 participants. In this period, 1308/1486 (88%) patients who were invited for participation in UMBRELLA consented to cohort participation. Of these patients, 1138 (87%) gave broad consent for randomization to future interventions. Return rate for PROs at baseline were 80%, and varied from 67 to 74% during follow-up. Several observational studies-and the first randomized intervention study-are currently ongoing. CONCLUSIONS: Results from UMBRELLA show that this novel study design is feasible and acceptable to patients in a clinical breast cancer setting. We invite researchers who are interested in conducting randomized or observational studies within the UMBRELLA cohort to contact the UMBRELLA scientific advisory board.

Risk of death from cardiovascular disease following breast cancer: a systematic review.

PURPOSE: Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer. METHODS: Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies. RESULTS: Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6-10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin. CONCLUSIONS: CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment.

18F-FDG PET as novel imaging biomarker for disease progression after ablation therapy in colorectal liver metastases.

PURPOSE: Recurrent disease following thermal ablation therapy is a frequently reported problem. Preoperative identification of patients with high risk of recurrent disease might enable individualized treatment based on patients' risk profile. The aim of the present work was to investigate the role of metabolic parameters derived from the pre-ablation 18F-FDG PET/CT as imaging biomarkers for recurrent disease in patients with colorectal liver metastases (CLM). METHODS: Included in this retrospective study were all consecutive patients with CLM treated with percutaneous or open thermal ablation therapy who had a pre-treatment baseline 18F-FDG PET/CT available. Multivariable cox regression for survival analysis was performed using different models for the metabolic parameters (SULpeak, SULmean, SULmax, partial volume corrected SULmean (cSULmean), and total lesion glycolysis (TLG)) corrected for tumour and procedure characteristics. The study endpoints were defined as local tumour progression free survival (LTP-FS), new intrahepatic recurrence free survival (NHR-FS) and extrahepatic recurrence free survival (EHR-FS). Clinical and imaging follow-up data was used as the reference standard. RESULTS: Fifty-four patients with 90 lesions were selected. Univariable cox regression analysis resulted in eight models. Multivariable analysis revealed that after adjusting for lesion size and the approach of the procedure, none of the metabolic parameters were associated with LTP-FS or EHR-FS. Percutaneous approach was significantly associated with a shorter LTP-FS. It was demonstrated that lower values of SULpeak, SULmax, SULmean , and cSULmean are associated with a significant better NHR-FS, independent of the lesion size and number and prior chemotherapy. CONCLUSION: We found no association between the metabolic parameters on pre-ablation 18F-FDG PET/CT and the LTP-FS. However, low values of the metabolic parameters were significantly associated with improved NHR-FS. The clinical implication of these findings might be the identification of high-risk patients who might benefit most from adjuvant or combined treatment strategies.

Redefining radiotherapy for early-stage breast cancer with single dose ablative treatment: a study protocol.

BACKGROUND: A shift towards less burdening and more patient friendly treatments for breast cancer is currently ongoing. In low-risk patients with early-stage disease, accelerated partial breast irradiation (APBI) is an alternative for whole breast irradiation following breast-conserving surgery. MRI-guided single dose ablative APBI has the potential to offer a minimally burdening, non-invasive treatment that could replace current breast-conserving therapy. METHODS: The ABLATIVE study is a prospective, single arm, multicenter study evaluating preoperative, single dose, ablative radiation treatment in patients with early-stage breast cancer. Patients with core biopsy proven non-lobular invasive breast cancer, (estrogen receptor positive, Her2 negative, maximum tumor size 3.0 cm on diagnostic MRI) and a negative sentinel node biopsy are eligible. Radiotherapy (RT) planning will be performed using a contrast enhanced (CE) planning CT-scan, co-registered with a CE-MRI, both in supine RT position. A total of twenty-five consecutive patients will be treated with a single ablative RT dose of 20 Gy to the tumor and 15 Gy to the tumorbed. Follow-up MRIs are scheduled within 1 week, 2, 4 and 6 months after single-dose RT. Breast-conserving surgery is scheduled at six months following RT. Primary study endpoint is pathological complete response. Secondary study endpoints are the radiological response and toxicity. Furthermore, patients will fill out questionnaires on quality of life and functional status. Cosmetic outcome will be evaluated by the treating radiation oncologist, patient and 'Breast Cancer Conservation Treatment cosmetic results' software. Recurrence and survival rates will be assessed. The patients will be followed up to 10 years after diagnosis. If patients give additional informed consent, a biopsy and a part of the irradiated specimen will be stored at the local Biobank and used for future research on radiotherapy response associated genotyping. DISCUSSION: The ABLATIVE study evaluates MRI-guided single dose ablative RT in patients with early-stage breast cancer, aiming at a less burdening and non-invasive alternative for current breast-conserving treatment. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT02316561 . The trial was registrated prospectively on October 10th 2014.

Systematic review and meta-analysis of the diagnostic accuracy of ductoscopy in patients with pathological nipple discharge.

BACKGROUND: Invasive surgery remains the standard for diagnosis of pathological nipple discharge (PND). Only a minority of patients with nipple discharge and an unsuspicious finding on conventional breast imaging have cancer. Ductoscopy is a minimally invasive alternative for evaluation of PND. This systematic review and meta-analysis was designed to evaluate the diagnostic accuracy of ductoscopy in patients with PND. METHODS: A systematic search of electronic databases for studies addressing ductoscopy in patients with PND was conducted. Two classification systems were assessed. For DSany , all visualized ductoscopic abnormalities were classified as positive, whereas for DSsusp , only suspicious findings were considered positive. After checking heterogeneity, pooled sensitivity and specificity of DSany and DSsusp were calculated. RESULTS: The search yielded 4642 original citations, of which 20 studies were included in the review. Malignancy rates varied from 0 to 27 per cent. Twelve studies, including 1994 patients, were eligible for meta-analysis. Pooled sensitivity and specificity of DSany were 94 (95 per cent c.i. 88 to 97) per cent and 47 (44 to 49) per cent respectively. Pooled sensitivity and specificity of DSsusp were 50 (36 to 64) and 83 (81 to 86) per cent respectively. Heterogeneity between studies was moderate to large for sensitivity (DSany : I2 = 17·5 per cent; DSsusp : I2 = 37·9 per cent) and very large for specificity (DSany : I2 = 96·8 per cent; DSsusp : I2 = 92·6 per cent). CONCLUSION: Ductoscopy detects about 94 per cent of all underlying malignancies in patients with PND, but does not permit reliable discrimination between malignant and benign findings.

Meta-analysis of the concordance of histological grade of breast cancer between core needle biopsy and surgical excision specimen.

BACKGROUND: With the increasing use of neoadjuvant chemotherapy and minimally invasive ablative therapy in breast cancer, pretreatment assessment of tumour grade on core needle biopsy (CNB) is increasingly needed. However, grading on CNB is possibly less accurate than grading based on the surgical excision specimen. A systematic review and meta-analysis of the literature was conducted to derive a reliable estimate of the agreement in tumour grading between CNB and subsequent surgical excision. METHODS: Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria, Embase, PubMed and the Cochrane Library were searched. Pooled proportions of agreement in grading between CNB and the excision specimen, Cohen's κ and percentages of overestimation and underestimation were calculated. Random-effects models were applied because of substantial heterogeneity, assessed by I2 test. Determinants of the level of agreement in grading were explored with meta-regression. RESULTS: Thirty-four articles were included in the systematic review (6029 patients) and 33 in the meta-analysis (4980 patients). Pooled agreement and κ were 71·1 (95 per cent c.i. 68·8 to 73·3) per cent and 0·54 (0·50 to 0·58) respectively. Underestimation and overestimation occurred in 19·1 (17·1 to 21·3) and 9·3 (7·7 to 11·4) per cent respectively. Meta-regression showed associations between agreement of histological type (positive association) and proportion of patients with oestrogen receptor-positive disease (negative association) and grade agreement. CONCLUSION: Grading on CNB corresponds moderately with grading based on excision specimens, with underestimation in about one in five patients. Incorrect CNB tumour grading has limited clinical implications, as multiple factors influence decision-making for adjuvant systemic therapy.