Oncology patients were found to understand and accept the Trials within Cohorts design

Background and Objective: The Trials within Cohorts design aims to reduce recruitment difficulties and disappointment bias in pragmatic trials. On cohort enrollment, broad informed consent for randomization is asked, after which cohort participants can be randomized to interventions or serve as controls without further notification. We evaluated patients' recollection, understanding, and acceptance of broad consent in a clinical oncology setting. Methods: We surveyed 610 patients with cancer participating in ongoing TwiCs; 482 patients (79%) responded, of which 312 patients shortly after cohort enrollment, 108 patients after randomization to an intervention (12-18 months after cohort enrollment), and a random sample of 62 cohort participants who had not been selected for interventions (1-6 months after cohort enrollment). Results: Shortly after providing cohort consent, 76% of patients (238/312) adequately remembered whether they had given broad consent for randomization. Of patients randomly offered interventions, 76% (82/108) remembered giving broad consent for randomization; 41% (44/108) understood they were randomly selected, 44% (48/108) were not interested in selection procedures, and 10% (11/108) did not understand selection was random. Among patients not selected for interventions, 42% (26/62) understood selection was random; 89% felt neutral regarding the scenario of "not being selected for an intervention while your data were being used in comparison with patients receiving interventions,"10% felt reassured (6/62) and 2% scared/insecure (2/62). Conclusion: Patients adequately remember giving broad consent for randomization shortly after cohort enrollment and after being offered an intervention, but recollection is lower in those never selected for interventions. Patients are acceptant of serving as control without further notifications. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21–26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3–24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-021-06314-4

Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors

Background: The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients. Materials and Methods: Plasma concentration-time data of paclitaxel were collected in patients with non - small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m2, or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m2. Data were analyzed using nonlinear mixed-effect modeling. Results: A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VMEL); patient age and total bilirubin were negatively correlated with VMEL (P < 0.005 for all correlations). Typically, male patients had a 20% higher VMEL; a 0.2 m2 increase of body surface area led to a 9% increase of VMEL; a 10-year increase of patient age led to a 5% decrease of VMEL; and a 10-μmol increase of total bilirubin led to a 14% decrease of VMEL. Third-space effusions were not correlated with paclitaxel pharmacokinetics. Conclusions: This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing. © 2006 American Association for Cancer Research

Clinical feasibility of a high-resolution thermal monitoring sheet for superficial hyperthermia in breast cancer patients

Background: Accurate monitoring of skin surface temperatures is necessary to ensure treatment quality during superficial hyperthermia. A high-resolution thermal monitoring sheet (TMS) was developed to monitor the skin surface temperature distribution. The influence of the TMS on applicator performance was investigated, feasibility and ability to reliably monitor the temperature distribution were evaluated in a clinical study. Methods: Phantom experiments were performed to determine the influence of the TMS on power deposition patterns, applicator efficiency, and heat transfer of the water bolus for 434 and 915 MHz applicators. Clinical feasibility was evaluated in 10 women with locoregional recurrent breast cancer. Skin surface temperatures during consecutive treatments were monitored alternatingly with either standard Amsterdam UMC thermometry or TMS. Treatments were compared using (generalized) linear mixed models. Results: The TMS did not significantly affect power deposition patterns and applicator efficiency (1–2%), the reduced heat transfer of the water boluses (51–56%) could be compensated by adjusting the water bolus flow. Skin surface temperatures were monitored reliably, and no alteration of thermal toxicity was observed compared to standard Amsterdam UMC thermometry. Conclusion: Clinical application of the TMS is feasible. Power deposition patterns and applicator efficiency were not affected. Surface temperatures were monitored reliably

Post-lumpectomy CT-guided tumor bed delineation for breast boost and partial breast irradiation : Can additional pre- and postoperative imaging reduce interobserver variability?

For breast boost radiotherapy or accelerated partial breast irradiation, the tumor bed (TB) is delineated by the radiation oncologist on a planning computed tomography (CT) scan. The aim of the present study was to investigate whether the interobserver variability (IOV) of the TB delineation is reduced by providing the radiation oncologist with additional magnetic resonance imaging (MRI) or CT scans. A total of 14 T1-T2 breast cancer patients underwent a standard planning CT in the supine treatment position following lumpectomy, as well as additional pre- and postoperative imaging in the same position. Post-lumpectomy TBs were independently delineated by four breast radiation oncologists on standard postoperative CT and on CT registered to an additional imaging modality. The additional imaging modalities used were postoperative MRI, preoperative contrast-enhanced (CE)-CT and preoperative CE-MRI. A cavity visualization score (CVS) was assigned to each standard postoperative CT by each observer. In addition, the conformity index (CI), volume and distance between centers of mass (dCOM) of the TB delineations were calculated. On CT, the median CI was 0.57, with a median volume of 22 cm(3) and dCOM of 5.1 mm. The addition of postoperative MRI increased the median TB volume significantly to 28 cm(3) (

The effects of exercise on the quality of life of patients with breast cancer (the UMBRELLA Fit study) : study protocol for a randomized controlled trial

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have shown that exercise has beneficial effects on quality of life (QoL) in patients with breast cancer. However, these effects were often small. Blinding in an exercise trial is not possible, which has the possible disadvantage of difficult accrual, drop-out after randomization to control and contamination between study groups (controls adopting the behaviour of the intervention group). The cohort multiple randomized controlled trial (cmRCT) is an alternative for conventional RCTs and has the potential to overcome these disadvantages. METHODS: This cmRCT will be performed within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA). Patients with breast cancer who visit the radiotherapy department of the University Medical Center Utrecht are asked to participate in UMBRELLA. Patients give consent for collection of medical information, providing patient-reported outcomes through regular questionnaires and randomization into future intervention studies. Patients who fulfill the UMBRELLA Fit study eligibility criteria (12 to 18 months post inclusion in UMBRELLA, low physical activity level) will be randomly allocated to the intervention or control group (1:1 ratio). Patients randomized to the intervention group will be offered a 12-week exercise programme. The control group will not be informed. Regular cohort measurements will be used for outcome assessment. Feasiblity (including participation, contamination, generalizability and retention) of the cmRCT design and effects of the intervention on QoL will be evaluated. DISCUSSION: We will examine the feasibility of the cmRCT design in exercise-oncology research and compare this with conventional RCTs. Furthermore, the effectiveness of an exercise intervention on the QoL of patients with breast cancer in the short term (6 months) and long term (24 months) will be studied. TRIAL REGISTRATION: Netherlands Trial Register, NTR5482/NL.52062.041.15 . Retrospectively registered on 7 December 2015

The effects of exercise on the quality of life of patients with breast cancer (the UMBRELLA Fit study) : study protocol for a randomized controlled trial

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have shown that exercise has beneficial effects on quality of life (QoL) in patients with breast cancer. However, these effects were often small. Blinding in an exercise trial is not possible, which has the possible disadvantage of difficult accrual, drop-out after randomization to control and contamination between study groups (controls adopting the behaviour of the intervention group). The cohort multiple randomized controlled trial (cmRCT) is an alternative for conventional RCTs and has the potential to overcome these disadvantages. METHODS: This cmRCT will be performed within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA). Patients with breast cancer who visit the radiotherapy department of the University Medical Center Utrecht are asked to participate in UMBRELLA. Patients give consent for collection of medical information, providing patient-reported outcomes through regular questionnaires and randomization into future intervention studies. Patients who fulfill the UMBRELLA Fit study eligibility criteria (12 to 18 months post inclusion in UMBRELLA, low physical activity level) will be randomly allocated to the intervention or control group (1:1 ratio). Patients randomized to the intervention group will be offered a 12-week exercise programme. The control group will not be informed. Regular cohort measurements will be used for outcome assessment. Feasiblity (including participation, contamination, generalizability and retention) of the cmRCT design and effects of the intervention on QoL will be evaluated. DISCUSSION: We will examine the feasibility of the cmRCT design in exercise-oncology research and compare this with conventional RCTs. Furthermore, the effectiveness of an exercise intervention on the QoL of patients with breast cancer in the short term (6 months) and long term (24 months) will be studied. TRIAL REGISTRATION: Netherlands Trial Register, NTR5482/NL.52062.041.15 . Retrospectively registered on 7 December 2015

Trends in the risk of cardiovascular disease in women with breast cancer in a Dutch nationwide cohort study

Objectives: To investigate trends in cardiovascular disease (CVD) risk following breast cancer using national registry data. Methods: A nationwide cohort study was conducted, comprising 163 881 women with in situ (7.6%) or invasive (92.4%) breast cancer and women of the general population, ranging from 3 661 141 in 1996 to 4 566 573 in 2010. CVD mortality rate in women with and without breast cancer and hospitalisation rate after breast cancer were calculated for the years 1996-2010. Age-adjusted CVD and breast cancer mortality within 5 years after breast cancer admission (1997-2010) were compared with 1996 calculated with a Cox proportional hazard analysis. Results: The absolute 10-year CVD mortality risk following breast cancer decreased from 56 per 1000 women in 1996 to 41 in 2005 (relative reduction=27.8%). In the general population, this decreased from 73 per 1000 women in 1996 to 55 in 2005 (-23.9%). The absolute risk of CVD hospitalisation within 1 year following breast cancer increased from 54 per 1000 women in 1996 to 67 in 2009 (+23.6%), which was largely explained by an increase in hospitalisation for hypertension, pulmonary embolism, rheumatoid heart/valve disease and heart failure. The 5-year CVD mortality risk was 42% lower (HR 0.58, 95% CI=0.48 to 0.70) for women admitted for breast cancer in 2010 compared with 1996. Conclusions: CVD mortality risk decreased in women with breast cancer and in women of the general population, with women with breast cancer having a lower risk of CVD mortality. By contrast, there was an increase in hospitalisation for CVD in women with breast cancer

Trends in the risk of cardiovascular disease in women with breast cancer in a Dutch nationwide cohort study

Objectives: To investigate trends in cardiovascular disease (CVD) risk following breast cancer using national registry data. Methods: A nationwide cohort study was conducted, comprising 163 881 women with in situ (7.6%) or invasive (92.4%) breast cancer and women of the general population, ranging from 3 661 141 in 1996 to 4 566 573 in 2010. CVD mortality rate in women with and without breast cancer and hospitalisation rate after breast cancer were calculated for the years 1996-2010. Age-adjusted CVD and breast cancer mortality within 5 years after breast cancer admission (1997-2010) were compared with 1996 calculated with a Cox proportional hazard analysis. Results: The absolute 10-year CVD mortality risk following breast cancer decreased from 56 per 1000 women in 1996 to 41 in 2005 (relative reduction=27.8%). In the general population, this decreased from 73 per 1000 women in 1996 to 55 in 2005 (-23.9%). The absolute risk of CVD hospitalisation within 1 year following breast cancer increased from 54 per 1000 women in 1996 to 67 in 2009 (+23.6%), which was largely explained by an increase in hospitalisation for hypertension, pulmonary embolism, rheumatoid heart/valve disease and heart failure. The 5-year CVD mortality risk was 42% lower (HR 0.58, 95% CI=0.48 to 0.70) for women admitted for breast cancer in 2010 compared with 1996. Conclusions: CVD mortality risk decreased in women with breast cancer and in women of the general population, with women with breast cancer having a lower risk of CVD mortality. By contrast, there was an increase in hospitalisation for CVD in women with breast cancer