Assessing the effect of hyperbaric oxygen therapy in breast cancer patients with late radiation toxicity (HONEY trial): a trial protocol using a trial within a cohort design

BACKGROUND: Breast cancer treatment with radiotherapy can induce late radiation toxicity, characterized by pain, fibrosis, edema, impaired arm mobility, and poor cosmetic outcome. Hyperbaric oxygen therapy (HBOT) has been proposed as treatment for late radiation toxicity; however, high-level evidence of effectiveness is lacking. As HBOT is standard treatment and reimbursed by insurers, performing classic randomized controlled trials is difficult. The "Hyperbaric OxygeN therapy on brEast cancer patients with late radiation toxicity" (HONEY) trial aims to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the trial within cohorts (TwiCs) design. METHODS: The HONEY trial will be conducted within the Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaluation (UMBRELLA). Within UMBRELLA, breast cancer patients referred for radiotherapy to the University Medical Centre Utrecht are eligible for inclusion. Patients consent to collection of clinical data and patient-reported outcomes and provide broad consent for randomization into future intervention studies. Patients who meet the HONEY in- and exclusion criteria (participation ≥ 12 months in UMBRELLA, moderate/severe breast or chest wall pain, completed primary breast cancer treatment except hormonal treatment, no prior treatment with HBOT, no contraindications for HBOT, no clinical signs of metastatic or recurrent disease) will be randomized to HBOT or control group on a 2:1 ratio (n = 120). Patients in the control group will not be informed about participation in the trial. Patients in the intervention arm will undergo 30-40 HBOT treatment sessions in a high pressure chamber (2.4 atmospheres absolute) where they inhale 100% oxygen through a mask. Cohort outcome measures (i.e., physical outcomes, quality of life, fatigue, and cosmetic satisfaction) of the HBOT group will be compared to the control group at 3 months follow-up. DISCUSSION: This pragmatic trial within the UMBELLA cohort was designed to evaluate the effectiveness of HBOT on late radiation toxicity in breast cancer patients using the TwiCs design. Use of the TwiCs design is expected to address issues encountered in classic randomized controlled trials, such as contamination (i.e., HBOT in the control group) and disappointment bias, and generate information about acceptability of HBOT. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04193722 . Registered on 10 December 2019

Axillary reverse mapping in axillary surgery for breast cancer: an update of the current status

Abstract Axillary reverse mapping (ARM) is a technique by which the lymphatic drainage of the upper extremity that traverses the axillary region can be differentiated from the lymphatic drainage of the breast during axillary lymph node dissection (ALND). Adding this procedure to ALND may reduce upper extremity lymphedema by preserving upper extremity drainage. This review of the current literature on the ARM procedure discusses the feasibility, safety and relevance of this technique. A PubMed literature search was performed until 12 August 2015. A total of 31 studies were included in this review. The studies indicated that the ARM procedure adequately identifies the upper extremity lymph nodes and lymphatics in the axillary basin using blue dye or fluorescence. Preservation of ARM lymph nodes and corresponding lymphatics was proven to be oncologically safe in clinically node-negative breast cancer patients with metastatic lymph node involvement in the sentinel lymph node (SLN) who are advised to undergo a completion ALND. The ARM procedure is technically feasible with a high visualisation rate using blue dye or fluorescence. ALND combined with ARM can be regarded as a promising surgical refinement in order to reduce the incidence of upper extremity lymphedema in selected groups of patients.<br/

Timing of surgical intervention in necrotizing pancreatitis

Objective: To determine the effect of timing of surgical intervention for necrotizing pancreatitis. Design: Retrospective study of 53 patients and a systematic review. Setting: A tertiary referral center. Main Outcome Measure: Mortality. Results: Median timing of the intervention was 28 days. Eighty-three percent of patients had infected necrosis and 55% had preoperative organ failure. The mortality rate was 36%. Sixteen patients were operated on within 14 days of initial admission, 11 patients from day 15 to 29, and 26 patients on day 30 or later. This latter group received preoperative antibiotics for a longer period (P <.001), and Candida species and antibiotic-resistant organisms were more often cultured from the pancreatic or peripancreatic necrosis in these patients (P = .02). The 30-day group also had the lowest mortality (8% vs 75% in the 1 to 14-days group and 45% in the 15 to 29 days group, P <.001); this difference persisted when outcome was stratified for preoperative organ failure. During the second half of the study, necrosectomy was further postponed (43 vs 20 days, P = .06) and mortality decreased (22% vs 47%, P = .09). We also reviewed 11 studies with a total of 1136 patients. Median surgical patient volume was 8.3 patients per year (range, 5.3-15.6), median timing of surgical intervention was 26 days (range, 3-31), and median mortality was 25% (range, 6%-56%). We observed a significant correlation between timing of intervention and mortality (R = -0.603; 95% confidence interval, -2.10 to -0.02; P = .05). Conclusion: Postponing necrosectomy until 30 days after initial hospital admission is associated with decreased mortality, prolonged use of antibiotics, and increased incidence of Candida species and antibiotic-resistant organisms

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

Breast Edema Following Breast-Conserving Surgery and Radiotherapy : Patient-Reported Prevalence, Determinants, and Effect on Health-Related Quality of Life

Background: The association between lymphedema of the arm and impaired health-related QoL (HR-QoL) has led to changes in clinical practice. However, data on lymphedema of the breast (ie, breast edema) are lacking. We prospectively evaluated patient-reported prevalence and determinants of breast edema and its effect on patient-reported HR-QoL and breast pain. Methods: We prospectively included 836 patients undergoing breast-conserving surgery followed by radiotherapy between October 2013 and October 2016 (UMBRELLA cohort). Patient-reported breast edema, HR-QoL, and breast pain were assessed by means of European Organisation for Research and Treatment of Cancer-C30/BR23 before starting radiotherapy and at 3, 6, 12, and 18 months thereafter. We assessed which patient, tumor, and treatment characteristics were associated with breast edema. With mixed-effects models, we assessed the impact of breast edema on patient-reported HR-QoL domains and breast pain over time, adjusting for confounders. Results: Within a median follow-up of 28 months (interquartile range [IQR] = 15), 207 (24.8%) patients reported breast edema at some point in time. Prevalence of breast edema was highest at 6 months (12.4%, 95% confidence interval [CI] = 10.0 to 14.7). Larger tumor size, oncoplastic surgery, axillary lymph node dissection, locoregional radiotherapy, radiotherapy boost on the tumor bed, and adjuvant chemotherapy were associated with breast edema. Breast edema was independently associated with more breast pain and with poorer QoL, physical functioning, and body image. Conclusions: Breast edema occurs frequently within the first year after breast-conserving surgery and radiotherapy and is independently associated with impaired HR-QoL and more breast pain. This information is important for use in clinical practice and should be discussed with patients during shared decision making

Self-reported work ability in breast cancer survivors; a prospective cohort study in the Netherlands

Purpose: To evaluate patient-reported work ability of breast cancer patients, to compare scores with the Dutch general population, and to identify determinants of reduced work ability in breast cancer patients. Methods: In a prospective cohort study, we identified 939 patients <67 years. Employed patients filled out the Work Ability Index (WAI) questionnaire before the start of radiotherapy treatment (baseline) and at 6, 18, and 30 months. Work ability was compared with a matched Dutch cancer-free population (n=3,641). The association between (clinical) characteristics and work ability over time was assessed using mixed-effects models. Results: At baseline, 68% (n=641) of the respondents were employed and 64% (n=203) were employed at 30 months. Moderate or poor work ability was reported by 71% of patients at baseline, by 24% of the patients at 30 months and by 14% of the general population. Axillary lymph node dissection, (neo)adjuvant chemotherapy and locoregional radiotherapy were associated with reduced work ability. After 30 months, 18% of employed patients reported to have reduced their working hours, made substantial modifications to their work or were unable to work. Conclusion: Patient-reported work ability is strongly reduced during breast cancer treatment. Thirty months after treatment the proportion of women reporting poor or moderate work ability remains higher compared to the general population. Even though the proportion of women with paid employment is rather stable over time, substantial amendments in work are needed in 18% of patients. These findings emphasize the importance of informing patients on potential changes in work ability to allow shared decision making

Self-reported work ability in breast cancer survivors; a prospective cohort study in the Netherlands

Purpose: To evaluate patient-reported work ability of breast cancer patients, to compare scores with the Dutch general population, and to identify determinants of reduced work ability in breast cancer patients. Methods: In a prospective cohort study, we identified 939 patients <67 years. Employed patients filled out the Work Ability Index (WAI) questionnaire before the start of radiotherapy treatment (baseline) and at 6, 18, and 30 months. Work ability was compared with a matched Dutch cancer-free population (n=3,641). The association between (clinical) characteristics and work ability over time was assessed using mixed-effects models. Results: At baseline, 68% (n=641) of the respondents were employed and 64% (n=203) were employed at 30 months. Moderate or poor work ability was reported by 71% of patients at baseline, by 24% of the patients at 30 months and by 14% of the general population. Axillary lymph node dissection, (neo)adjuvant chemotherapy and locoregional radiotherapy were associated with reduced work ability. After 30 months, 18% of employed patients reported to have reduced their working hours, made substantial modifications to their work or were unable to work. Conclusion: Patient-reported work ability is strongly reduced during breast cancer treatment. Thirty months after treatment the proportion of women reporting poor or moderate work ability remains higher compared to the general population. Even though the proportion of women with paid employment is rather stable over time, substantial amendments in work are needed in 18% of patients. These findings emphasize the importance of informing patients on potential changes in work ability to allow shared decision making