Danny A. Young-Afat

Brief Report : Staged-informed Consent in the Cohort Multiple Randomized Controlled Trial Design

The “cohort multiple randomized controlled trial,” a new design for pragmatic trials, embeds multiple trials within a cohort. The cohort multiple RCT is an attractive alternative to conventional RCTs in fields where recruitment is slow, multiple new (competing) interventions for the same condition have to be tested, new interventions are highly preferred by patients and doctors, and the risk of disappointment bias, cross-over, and contamination is considerable. To prevent these unwanted effects, the cohort multiple RCT provides information on randomization to the intervention group/arm only, and only after randomization (i.e., prerandomization). To some, especially in a clinical setting, this is not ethically acceptable. In this article, we argue that prerandomization in the cohort multiple randomized controlled trial (cmRCT) can be avoided by adopting a staged-informed consent procedure. In the first stage, at entry into the cohort, all potential participants are asked for their informed consent to participate in a cohort study and broad consent to be either randomly selected to be approached for experimental interventions or to serve as control without further notice during participation in the cohort. In a second stage, at the initiation of an RCT within the cohort, informed consent to receive the intervention is then only sought in those randomly selected for the intervention arm. At the third stage, after completion of each RCT, all cohort participants receive aggregate disclosure of trial results. This staged-informed consent procedure avoids prerandomization in cmRCT and aims to keep participants actively engaged in the research process.

The cohort multiple randomized controlled trial design: a valid and efficient alternative to pragmatic trials?

Randomized controlled trials (RCTs)-the gold standard for evaluating the effects of medical interventions-are notoriously challenging in terms of logistics, planning and costs. The cohort multiple randomized controlled trial approach is designed to facilitate randomized trials for pragmatic evaluation of (new) interventions and is a promising variation from conventional pragmatic RCTs. In this paper, we evaluate methodological challenges of conducting an RCT within a cohort. We argue that equally valid results can be obtained from trials conducted within cohorts as from pragmatic RCTs. However, whether this design is more efficient compared with conducting a pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm.

Just-in-time consent: The ethical case for an alternative to traditional informed consent in randomized trials comparing an experimental intervention with usual care:

Informed consent for randomized trials often causes significant and persistent anxiety, distress and confusion to patients. Where an experimental treatment is compared to a standard care control, much of this burden is potentially avoidable in the control group. We propose a “just-in-time” consent in which consent discussions take place in two stages: an initial consent to research from all participants and a later specific consent to randomized treatment only from those assigned to the experimental intervention. All patients are first approached and informed about research procedures, such as questionnaires or tests. They are also informed that they might be randomly selected to receive an experimental treatment and that, if selected, they can learn more about the treatment and decide whether or not to accept it at that time. After randomization, control patients undergo standard clinical consent whereas patients randomized to the experimental procedure undergo a second consent discussion. Analysis would be by intent-to-treat, which protects the trial from selection bias, although not from poor acceptance of experimental treatment. The advantages of just-in-time consent stem from the fact that only patients randomized to the experimental treatment are subject to a discussion of that intervention. We hypothesize that this will reduce much of the patient’s burden associated with the consent process, such as decisional anxiety, confusion and information overload. We recommend well-controlled studies to compare just-in-time and traditional consent, with endpoints to include characteristics of participants, distress and anxiety and participants’ understanding of research procedures.

The ethics of ‘Trials within Cohorts’ (TwiCs): 2nd international symposium

On 7-8 November 2016, 60 people with an interest in the ‘Trials within Cohorts’ (TwiCs) approach for randomised controlled trial design met in London. The purpose of this 2 TwiCs international symposium was to share perspectives and experiences on ethical aspects of the TwiCs design, discuss how TwiCs relate to the current ethical framework, provide a forum in which to discuss and debate ethical issues and identify future directions for conceptual and empirical research. The symposium was supported by the Wellcome Trust and the NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton and attended by people from the UK, the Netherlands, Norway, Canada and USA. The two-day symposium enabled an international group to meet and share experiences of the TwiCs design (also known as the ‘cohort multiple RCT design’), and to discuss plans for future research. Over the two days, invited plenary talks were interspersed by discussions, posters and mini presentations from bioethicists, triallists and health research regulators. Key findings of the symposium were: (1) It is possible to make a compelling case to ethics committees that TwiCs designs are appropriate and ethical; (2) The importance of wider considerations around the ethics of inefficient trial designs; and (3) some questions about the ethical requirements for content and timing of informed consent for a study using the TwiCs design need to be decided on a case-by-case basis. Main report On 7-8 November 2016, 60 people with an interest in the ‘Trials within Cohorts’ (TwiCs) design met in London for the 2 TwiCs international symposium. The symposium was supported by the Wellcome Trust and NIHR CLAHRC Yorkshire and Humber and organised by members of the TwiCs network led by Clare Relton. As well as UK participants, people came from the Netherlands, Norway, Canada and USA. Over the two days, the invited plenary talks were interspersed by discussions, posters and mini presentations from bioethicists, triallists and health research regulators.

Quality of life and patient satisfaction after one-stage implant-based breast reconstruction with an acellular dermal matrix versus two-stage breast reconstruction (BRIOS): primary outcome of a randomised, controlled trial

BACKGROUND There is increasing interest in the use of acellular dermal matrices (ADMs) in implant-based breast reconstruction (IBBR). Suggested advantages are that ADMs facilitate one-stage IBBR and improve aesthetic outcomes. We compared immediate one-stage ADM-assisted IBBR with two-stage IBBR (current standard of care). Our previously reported secondary endpoint showed that one-stage ADM-assisted IBBR was associated with significantly more adverse outcomes. Here, we present the primary endpoint results aiming to assess whether one-stage IBBR with ADM provides higher patient-reported quality of life (QOL) compared with two-stage IBBR. METHODS This multicentre, open-label, randomised controlled trial (BRIOS study) was done in eight hospitals in the Netherlands. We recruited women aged older than 18 years with breast carcinoma or a genetic predisposition who intended to undergo skin-sparing mastectomy and immediate IBBR. Participants were randomly assigned to undergo one-stage IBBR with ADM (Strattice, LifeCell, Branchburg, NJ, USA) or two-stage IBBR. Randomisation was stratified by centre and indication for surgery (oncological or prophylactic) in blocks of ten participants. The primary endpoint was patient-reported QOL, as measured with the BREAST-Q (ie, health-related QOL scales and satisfaction scales), in the modified intention-to-treat population. The study follow-up is complete. This study is registered with the Netherlands Trial Register, number NTR5446. FINDINGS Between April 14, 2013, and May 29, 2015, we enrolled 142 women, of whom 69 were randomly assigned to receive one-stage ADM-assisted IBBR and 73 to receive two-stage IBBR. After exclusions, the modified intention-to-treat population comprised 60 patients in the one-stage group and 61 patients in the two-stage group. Of these, 48 women (mean follow-up 17·0 months [SD 7·8]) in the one-stage group and 44 women (17·2 months [SD 6·7]) in the two-stage group completed the BREAST-Q at least 1 year after implant placement. We found no significant differences in postoperative patient-reported QOL domains, including physical wellbeing (one-stage mean 78·0 [SD 14·1] vs two-stage 79·3 [12·2], p=0·60), psychosocial wellbeing (72·6 [17·3] vs 72·8 [19·6], p=0·95), and sexual wellbeing (58·0 [17·0] vs 57·1 [19·5], p=0·82), or in the patient-reported satisfaction domains: satisfaction with breasts (63·4 [15·8] vs 60·3 [15·4], p=0·35) and satisfaction with outcome (72·8 [19·1] vs 67·8 [16·3], p=0·19). INTERPRETATION Taken together with our previously published findings, one-stage IBBR with ADM does not yield superior results in terms of patient-reported QOL compared with two-stage IBBR. Risks for adverse outcomes were significantly higher in the one-stage ADM group. Use of ADM for one-stage IBBM should be considered on a case-by-case basis. FUNDING Pink Ribbon, Nuts-Ohra, and LifeCell.

Impact of modern-day axillary treatment on patient reported arm morbidity and physical functioning in breast cancer patients

PURPOSE To reduce arm morbidity, routine axillary lymph node dissection (ALND) is often omitted or replaced by axillary radiotherapy (AxRT) in patients with limited nodal involvement. We evaluated patient-reported arm morbidity and physical functioning in breast cancer patients undergoing modern-day axillary treatment. METHODS All patients within the UMBRELLA cohort undergoing local radiotherapy with sentinel lymph node biopsy (SLNB), ALND and/or AxRT were selected. Patient-reported arm morbidity and physical functioning were assessed with EORTC QLQ C30/BR23 questionnaires up to eighteen months after initiation of radiotherapy. Patient-reported outcomes were compared between patients with SLNB only, ALND only, AxRT (level I-II), AxRT (level I-IV) or AxRT plus ALND by means of mixed model analysis. RESULTS In total, 949 patients were identified; 641 (68%) SLNB only, 57 (6%) ALND only, 94 (10%) AxRT level I-II, 72 (8%) AxRT level I-IV and 85 (9%) ALND + AxRT. SLNB only resulted in the least arm morbidity scores. ALND + AxRT resulted in most arm morbidity, with clinically relevant differences at 18 months. AxRT (level I-II or level I-IV) resulted in significantly less arm symptoms in the first 3 months compared to ALND. Arm symptom scores between those receiving AxRT on levels I-II and I-IV were similar. CONCLUSION Of all axillary management strategies, ALND plus AxRT is associated with worst patient-reported outcomes. AxRT resulted in less arm morbidity compared to ALND. Selective radiotherapy treatment of the axilla, i.e. radiotherapy of levels I-II only instead of levels I-IV, did not lead to clinically relevant reduced arm morbidity.

Determinants of satisfaction with cosmetic outcome in breast cancer survivors: A cross-sectional study

Little research has been done into cosmetic outcomes in non-Western breast cancer populations. We aimed to study the prevalence and determinants of dissatisfaction with cosmetic outcome after breast cancer surgery of Asian breast cancer survivors, and its association with patient-reported anxiety, depression, and quality of life. In a hospital-based cross-sectional study, 384 breast cancer survivors of at least 12 months after diagnosis completed questionnaires on satisfaction with cosmetic appearance, quality of life (EORTC-QLQ-C30) and anxiety and depression (HADS). Cumulative logit models were used to examine the adjusted association between dissatisfaction with cosmetic appearance and demographic and clinical characteristics. Kruskal-Wallis test was used to test for associations between dissatisfaction with cosmetic appearance and patient-reported outcomes. Overall, 20% of women reported to be (very) dissatisfied with cosmetic appearance. Survivors of Chinese ethnicity were more likely dissatisfied with cosmetic appearance compared to Malay survivors (22% and 14% respectively, adjusted OR = 2.4, 95%CI: 1.4–3.9). Women with DCIS (adjusted OR = 2.2, 95%CI: 1.3–3.7) or advanced stage disease (adjusted OR = 2.2, 95%CI: 1.2–3.9) had a higher risk of being dissatisfied with their cosmetic appearance. Women treated with mastectomy were at a higher risk of dissatisfaction with cosmetic appearance (adjusted OR = 1.7, 95%CI: 1.1–2.5). Dissatisfaction with cosmetic appearance was associated with increased depression scores. In this South-East Asian population, one in five breast cancer patients were (very) dissatisfied with the cosmetic outcome of treatment. Chinese women, women with larger tumors and women treated with mastectomy were most likely to report dissatisfaction with cosmetic appearance.

Autologous breast reconstruction in sickle cell trait: A fine line between success & failure

Autologous breast reconstructions are increasingly being performed. While increased risks for flap loss after free tissue transfer (FTT) in sickle cell patients are known to most plastic surgeons, risks for patients with sickle cell trait (SCT) are less known. Unfortunately, recommendations to prevent complications after FTT in SCT are still scarce. We present additional and novel surgical measures that we took aiming to enhance probabilities for successful FTT in a SCT patient undergoing autologous breast reconstruction. This is only the second case report describing a successful FTT without flap necrosis/loss in a patient with SCT, and the first successful report involving FTT in the breast.

Nipple-sparing mastectomy using a hemi-periareolar incision – Comment on the BREAST-Q analysis

With great interest we have read the article about nipplesparing mastectomy using a hemi-periareolar incision with or without minimal medial-lateral extensions by El Hage Chehade et al.1 The authors report on the clinical outcomes and patient satisfaction after immediate reconstruction with implants and acellular dermal matrix. Patient satisfaction was assessed with the BREAST-Q.2 However, results from this study are difficult to interpret, since the authors do not provide BREAST-Q scores obtained from the recommended Rasch Measurement Theory analysis (as automatically performed when using the recommended Q-score software). Instead, the authors converted crude BREAST-Q scores into percentages, of which a score 75% corresponded to being very satisfied, 50%e74% to a satisfied result and <50% to a dissatisfaction with the outcome. In order to clearly interpret their results, and to properly compare their results with other (future) studies with BREAST-Q as outcome, we suggest for the authors to report the crude BREAST-Q scores (as obtained by the Q-score software). Reducing heterogeneity in study outcomes is an important step towards better comparability between studies.3

Abstract P3-12-23: Breast and chest wall edema during and following radiotherapy in breast cancer patients: Prevalence, risk factors and quality of life

PURPOSE/OBJECTIVE Innovations in loco-regional breast cancer treatment, such as oncoplastic surgery and neoadjuvant chemotherapy, have been suggested to increase the risk of breast and chest wall edema, which may impair quality of life (QoL) during and after treatment. The objective of this study is to evaluate prevalence and risk factors of breast and chest wall edema and its effect on quality of life. METHODS We conducted this study within a prospective observational cohort of breast cancer patients indicated to undergo radiation treatment after being treated with surgery (Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation, UMBRELLA). At the time of inclusion all participants consented to the collection of clinical data and 9patient reported outcomes9 (PROMs) at regular intervals during and after treatment. Presence of breast and chest wall edema was registered by radiation oncologists according to CTCAE V4.0 scoring system, at weekly follow-up visits during radiation treatment, and at standard follow-up intervals after radiation treatment. When present, edema was defined as 9acute9 (i.e. breast and chest wall edema within 0-90 days after the start of radiation treatment), 9late9 (i.e. >90 days) or both. Information on potential risk factors, such as patient and tumor characteristics, and treatment (e.g. surgical procedure, RT target volumes, (neo)adjuvant chemotherapy) was collected from electronic patient files and questionnaires. We performed univariate and multivariable logistic regression analysis to identify determinants that were (independently) associated with breast and chest wall edema. PROMs on quality of life and pain (i.e. EORTC QLQ-C30/BR23) were collected regularly (i.e. baseline, 3, 6 and 12 months) and compared between patients with and without edema. RESULTS We included 427 patients with at least 3 months follow-up (median follow-up 48 weeks). Sixteen percent (70/427) had acute edema, 23% (73/314) had late edema and 8% (25/314) had both acute and late edema. The proportion of women with acute edema was significantly higher in patients treated with oncoplastic surgery (31% vs. 15%, p=0.03) or mastectomy (31% vs. 14% p CONCLUSION Breast and chest wall edema is associated with reduced quality of life during the first year of treatment. Oncoplastic surgery and mastectomy increase the risk for acute edema, while oncoplastic surgery, mastectomy, axillary treatment (i.e. ALND, radiation therapy) and the presence of acute edema are associated with late edema. Early treatment of acute edema may reduce the risk for late edema, prolonged pain and impaired quality of life. Citation Format: Young-Afat DA, Verkooijen HM, Gregorowitsch ML, van Gils CH, van der Pol CC, Witkamp AJ, Burgmans I, Jonasse Y, van Vulpen M, van den Bongard DJ. Breast and chest wall edema during and following radiotherapy in breast cancer patients: Prevalence, risk factors and quality of life. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-23.