The Effect of Intraoperative Margin Assessment During Breast Conserving Surgery for Breast Cancer in a Dutch Cohort.

INTRODUCTION: Intraoperative specimen radiography is a routinely used procedure to ensure adequate resection of non-palpable breast tumors. Intraoperative digital specimen mammography (IDSM) is an alternative to conventional specimen radiography (CSR) which provides immediate specimen evaluation and can potentially decrease operation time. IDSM may also result in lower positive margin and re-excision rates. IDSM was implemented in our hospital in 2018. The objective of this study was to evaluate the effect of using IDSM versus CSR on operation time, margin status and re-excision rates in breast conserving surgery. METHODS: The present study is a single-center retrospective cohort study with 2 patient cohorts: one which underwent CSR (n = 532) and one which underwent IDSM (n = 475). The primary outcome was the operation time. Secondary outcomes were the margin status of the primary surgery, the cavity shaving rate, and the re-excision rate. Differences between cohorts were compared using univariate statistics and multiple regression analyses to adjust for variables that were significantly different between the groups. RESULTS: IDSM use was associated with an 8-minute reduction in surgery time (B = -8.034, 95% CI [-11.6, -4.5]; P < .001). Treatment variables independently associated with the operation time included use of IDSM, type of surgery, and performance of cavity shaving. Cavity shaves were more often performed when IDSM was used (24% for IDSM vs. 14% for CSR, P < .001), while the proportion of negative margin rates (93% for IDSM vs. 96% for CSR, P = .070) was comparable. CONCLUSION: IDSM was associated with a modest reduction in operation time. Surgeons performed more cavity shaves since the introduction of IDSM, but this increase was not reflected by difference in negative margin rates.

Implementation of vacuum-assisted excision as a management option for benign and high-risk breast lesions.

OBJECTIVE: Previous studies have shown that vacuum-assisted excision (VAE) is a safe and effective alternative for surgical excision (SE) of benign breast lesions. However, the use of VAE in high-risk lesions is controversial and guidelines are ambiguous. This study describes the impact of the implementation of VAE in terms of management and outcomes compared to a cohort before implementation. METHODS: A single centre retrospective study with two cohorts: 'before' and 'after' implementation of VAE was performed. All patients with a benign or high-risk lesion treated by VAE or SE between 2016 and 2019 were included. Excision, complication, and upgrade rates were compared between both cohorts. Cox regression was used for the evaluation of recurrences and re-excisions. RESULTS: The overall excision rate of all benign and high-risk lesions was comparable in both cohorts (17% vs 16%, p = 0.700). After implementation, benign lesions were significantly more often managed by VAE (101/151, 67%, p < 0.001). Re-excision, recurrence, and complication rates were low and comparable between cohorts (4.3% vs 3.9%, p > 0.999; 3.0 vs 2.0%, p = 0.683; 3.4 vs 6.6%, p = 0.289, respectively). CONCLUSION: SE could safely be replaced by VAE in 58% of patients treated for a benign or high-risk lesion. With this shift in management, the use of operating rooms and general anaesthesia can safely be omitted in this patient group. Further research on high-risk lesions is warranted since our data are exploratory. ADVANCES IN KNOWLEDGE: This study provides supportive data for the use of VAE as a management option for both benign (up to 5 cm) and high-risk lesions. Outcomes on re-excision, recurrence should be confirmed in prospective studies especially in high-risk lesions.

Hospital costs and cosmetic outcome of benign and high-risk breast lesions managed by vacuum-assisted excision versus surgical excision.

OBJECTIVES: Although vacuum-assisted excision (VAE) is a safe and effective alternative to surgical excision (SE), the latter is most commonly used for the management of benign and high-risk breast lesions. To evaluate the healthcare benefit of VAE, hospital costs and cosmetic outcome after VAE were compared to SE. Additionally, the impact of VAE implementation on hospital costs was investigated. METHODS: This was a single-centre retrospective cohort study with two cohorts: "VAE" and "SE". All patients with a benign or high-risk lesion excised by VAE or SE from January 2016 up to December 2019 were included. Cosmetic outcome was measured with the BCTOS-cosmetic subscale, and hospital costs were presented as mean (SD) and median (IQR). RESULTS: During the study period, 258 patients with 295 excised lesions were included. The initial procedure was VAE in 102 patients and SE in 156 patients. Hospital costs after (median € 2324) were significantly lower than before (median € 3,144) implementation of VAE (mean difference € 1,004, p < 0.001), most likely attributable to the lower costs for patients treated with VAE (mean difference € 1,979, p < 0.001). Mean cosmetic outcome was comparable between VAE (median 1.35) and SE (median 1.44, p = 0.802). CONCLUSIONS: Implementing VAE as an alternative treatment option for benign and high-risk breast lesions resulted in a large decrease in hospital costs but a cosmetic benefit of VAE could not be demonstrated in this retrospective study. ADVANCES IN KNOWLEDGE: Costs associated with the complete patient pathway were included and not only VAE was compared to SE but also the before cohort was compared to the after cohort to demonstrate the benefit of VAE implementation in clinical practice. Additionally, cosmetic outcome was compared between VAE and SE using patient reported outcome measures.

Treatment of early-stage breast cancer with percutaneous thermal ablation, an open-label randomised phase 2 screening trial: rationale and design of the THERMAC trial.

INTRODUCTION: Breast cancer is the most frequently diagnosed malignancy worldwide but almost half of the patients have an excellent prognosis with a 5-year survival rate of 98%-99%. These patients could potentially be treated with thermal ablation to avoid surgical excision, reduce treatment-related morbidity and increase patients' quality of life without jeopardising treatment effectiveness. Previous studies showed highest complete ablation rates for radiofrequency, microwave and cryoablation. However, due to heterogeneity among studies, it is unknown which of these three techniques should be selected for a phase 3 comparative study. METHODS AND ANALYSIS: The aim of this phase 2 screening trial is to determine the efficacy rate of radiofrequency, microwave and cryoablation with the intention to select one treatment for further testing in a phase 3 trial. Additionally, exploratory data are obtained for the phase 3 trial. The design is a multicentre open-label randomised phase 2 screening trial. Patients with unifocal, invasive breast cancer with a maximum diameter of 2 cm without lymph node or distant metastases are included. Triple negative, Bloom-Richardson grade 3 tumours and patients with an indication for neoadjuvant chemotherapy will be excluded. Included patients will be allocated to receive one of the three thermal ablation techniques. Three months later surgical excision will be performed to determine the efficacy of thermal ablation. Treatment efficacy in terms of complete ablation rate will be assessed with CK 8/18 and H&E staining. Secondary outcomes include feasibility of the techniques in an outpatient setting, accuracy of MRI for complete ablation, patient satisfaction, adverse events, side effects, cosmetic outcome, system usability and immune response. ETHICS AND DISSEMINATION: This study protocol was approved by Medical Research Ethics Committee of the Erasmus Medical Center, Rotterdam, the Netherlands. Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9205 (www.trialregister.nl); Pre-results.

Randomized controlled trial comparing magnetic marker localization (MaMaLoc) with wire-guided localization in the treatment of early-stage breast cancer.

Wire-guided localization (WGL) is the standard of care in the surgical treatment of nonpalpable breast tumors. In this study, we compare the use of a new magnetic marker localization (MaMaLoc) technique to WGL in the treatment of early-stage breast cancer patients. Open-label, single-center, randomized controlled trial comparing MaMaLoc (intervention) to WGL (control) in women with early-stage breast cancer. Primary outcome was surgical usability measured using the System Usability Scale (SUS, 0-100 score). Secondary outcomes were patient reported, clinical, and pathological outcomes such as retrieval rate, operative time, resected specimen weight, margin status, and reoperation rate. Thirty-two patients were analyzed in the MaMaLoc group and 35 in the WGL group. Patient and tumor characteristics were comparable between groups. No in situ complications occurred. Retrieval rate was 100% in both groups. Surgical usability was higher for MaMaLoc: 70.2 ± 8.9 vs. 58.1 ± 9.1, p < 0.001. Patients reported higher overall satisfaction with MaMaLoc (median score 5/5) versus WGL (score 4/5), p < 0.001. The use of magnetic marker localization (MaMaLoc) for early-stage breast cancer is effective and has higher surgical usability than standard WGL.

Thermal Ablation as an Alternative for Surgical Resection of Small (≤ 2 cm) Breast Cancers: A Meta-Analysis.

Women with early-stage breast cancer have an excellent prognosis with current therapy, but could presumably be treated less invasively, without the need for surgery. The primary goal of this meta-analysis was to examine whether thermal ablation is an effective method to treat early-stage breast cancer. Studies reporting on complete ablation rate after thermal ablation as a treatment of small breast cancers (≤ 2 cm) were included. Methodologic quality of included studies was assessed using MINORS criteria. Complete ablation rates are given as proportions, and meta-regression and subgroup analyses were performed. The overall complete ablation rate in 1266 patients was 86% and was highest after radiofrequency ablation (RFA) (92%). Local recurrence rates varied from 0% to 3%, with a median follow-up of 15 to 61 months. Overall, complication rates were low (5%-18% across techniques) and were highest after high-intensity focused ultrasound ablation and lowest after cryoablation. Cosmetic outcome was good to excellent in at least 85% of patients but was reported infrequently and long-term results of cosmetic outcome after thermal ablation and radiotherapy are still lacking. Thermal ablation techniques treating early-stage breast cancer (≤ 2 cm) are safe and effective based on complete ablation rate and short-term local recurrence rates. Especially, RFA, microwave ablation, and cryoablation are promising techniques as an alternative to surgical resection without jeopardizing current treatment effectiveness or safety. Owing to great heterogeneity in the included studies, a formal recommendation on the best technique is not possible. These findings warrant the design of large randomized controlled trials comparing thermal ablation and breast-conserving surgery in the treatment of T1 breast cancer.

Patient reported cosmetic outcome after vacuum assisted excision of benign breast lesions: a cross-sectional study.

OBJECTIVE: Better cosmetic outcome after vacuum assisted excision (VAE) compared to surgical excision of benign breast lesions is suggested in previous studies but has never been evaluated with validated outcome measures. In this study, patient reported cosmetic outcome after VAE was evaluated. METHODS: Patients who underwent VAE between July 2017 and December 2018 were invited to complete the cosmetic subscale of the Dutch Breast Cancer Treatment Outcome Scale, comparing the treated with the untreated breast. Response mode ranged from 1 (no difference) to 4 (large difference) and cosmetic outcome was calculated as the unweighted mean. Clinical outcomes included: tumor size, number of cores, complications, residual lesions and recurrences. RESULTS: Response rate was 73.4% (47 of 64 patients). Median tumor size was 15 mm (range 5-51 mm) and median number of cores 6.5 (range 1-85), complete excision was confirmed in all but two patients. Mean cosmetic outcome was good (mean score ≤1.75) in 74% of patients and no patients reported a poor cosmetic outcome (mean score >3.25). A hematoma occurred in five patients (one needed aspiration) and a skin rash in one patient, no patients developed an infection or seroma. CONCLUSION: In this study VAE is safe and effective for tumors up to 5 cm and patient reported cosmetic outcome was good. Patients with benign lesions could benefit from VAE as an alternative for surgical excision. ADVANCES IN KNOWLEDGE: A formal quantitative measurement of cosmetic outcome after vacuum assisted excision for benign breast lesions was still lacking. This study shows that this cosmetic outcome is overall good in benign lesions up to 5 cm.

Radiochromic film in vivo dosimetry predicts early the risk of acute skin toxicity for brachytherapy partial breast irradiation.

Brachytherapy accelerated partial breast irradiation (APBI) is well tolerated, but reported acute toxicities including moist desquamation rates range from 7% to 39%. Moist desquamation is correlated to long-term skin toxicity and high skin dose is the main risk factor. This study uses radiochromic films for in vivo skin dosimetry of low dose rate (LDR) APBI brachytherapy and prediction of skin toxicity. Patients participating in a clinical trial assessing skin toxicity of LDR seed brachytherapy were included in this study. Following the seed implantation procedure, patients were asked to wear a customized oval shaped radiochromic film on the skin projection of the planned target volume (PTV) for 24 h. Exposed films were collected, and maximum point doses were measured. In addition, maximum doses to a small skin volume (D0.2cc) were calculated on the pre- and post-implant CT-scan. Acute skin toxicities (redness, pigmentation, induration and dermatitis) were scored by the treating physician for 2 months during follow-up visits. Skin dose measurements and acute toxicity were available for 18 consecutive patients. The post-implant calculated maximum skin doses (D0.2cc), 60.8 Gy (SD ± 41.0), were on average 30% higher than those measured in vivo (Dmax-film), 46.6 Gy (SD ± 19.3), but those values were highly significantly correlated (Spearman's rho 0.827, p < 0.001). Also, dermatitis and induration were significantly correlated with higher in vivo measured and post-implant calculated skin dose. Pre-implant dosimetry was not correlated with measured or post-implant skin dose or side effects. Radiochromic films can reliably diagnose excess dose to the skin during the first 24 h and predict skin toxicity, which enables preventative measures. Trial registration: Nederlands Trial Register (www.trialregister.nl), NTR6549, the trial was registered prospectively on 27 June 2017. ABR number: NL56210.078.16.

Injection of radiopaque hydrogel at time of lumpectomy improves the target definition for adjuvant radiotherapy.

BACKGROUND AND PURPOSE: During oncoplastic breast-conserving surgery (BCS), the surgical cavity is closed to reduce seroma formation. This makes the radiotherapy target definition using clips challenging, leading to poor inter-observer agreement and potentially geographical misses. We hypothesize that injecting a radiopaque hydrogel in the lumpectomy cavity before closure improves radiotherapy target definition and agreement between observers. MATERIALS AND METHODS: Women undergoing BCS in a single university hospital were prospectively accrued in the study. Three to 9 ml of iodined PolyEthylene Glycol (PEG) hydrogel and clips were inserted in the lumpectomy cavity. A CT-scan was performed at 4 to 6 weeks. CT images of BCS patients with standard clips only were used as control group, matched on age, specimen weight, and distance between clips. Six radiation oncologists delineated the tumor bed volumes and rated the cavity visualization scores (CVS). The primary endpoint was the agreement between observers measured using a Conformity Index (Cx). RESULTS: Forty-two patients were included, 21 hydrogel procedures and 21 controls, resulting in 315 observer pairs. The feasibility of the intervention was 100%. The median Cx was higher in the intervention group (Cx = 0.70, IQR [0.54-0.79]) than in the control group (Cx = 0.54, IQR [0.42-0.66]), p < 0.00, as were the CVS (3.5 [2.5-4.5] versus 2.5 [2-3.5], p < 0.001). The rate of surgical site infections was similar to literature. CONCLUSIONS: The use of radiopaque PEG enables to identify the lumpectomy cavity, resulting in a high inter-observer agreement for radiotherapy target definition. This intervention is easy to perform and blend well into current practice.

Subcutaneous spacer injection to reduce skin toxicity in breast brachytherapy: A pilot study on mastectomy specimens.

PURPOSE: Accelerated partial breast irradiation is a treatment option for selected patients with early-stage breast cancer. Some accelerated partial breast irradiation techniques lead to skin toxicity with the skin dose as a main risk factor. Biodegradable spacers are effective and safe in prostate brachytherapy to protect the rectum. We hypothesize that a subcutaneous spacer injection reduces the skin dose in breast brachytherapy. METHODS AND MATERIALS: Ultrasound-guided spacer injections, either hyaluronic acid (HA) or iodined polyethylene glycol (PEG), were performed on fresh mastectomy specimens. Success was defined as a spacer thickness of ≥5 mm in the high-dose skin area. Usability was scored using the system usability scale. Pre and postinjection CT scans were used to generate low-dose-rate seed brachytherapy treatment plans after defining a clinical target volume. Maximum dose to small skin volumes (D0.2cc) and existence of hotspots (isodose ≥90% on 1 cm2 of skin) were calculated as skin toxicity indicators. RESULTS: We collected 22 mastectomy specimens; half had HA and half had PEG injection. Intervention success was 100% for HA and 90.9% for PEG (p = NS). Hydrodissection was feasible in 81.8% with HA and 63.6% with PEG. Median system usability scale score was 97.5 for HA and 82.5 for PEG (p < 0.001). Mean D0.2cc was 80.8 Gy without spacer and 53.7 Gy with spacer (p < 0.001). Skin hotspots were present in 40.9% without spacer but none with spacer (p < 0.001). CONCLUSIONS: A spacer injection in mastectomy specimens is feasible. An extra 5 mm space is always achieved, thereby potentially reducing the skin dose dramatically in low-dose-rate seed breast brachytherapy.

A randomized controlled trial testing a hyaluronic acid spacer injection for skin toxicity reduction of brachytherapy accelerated partial breast irradiation (APBI): a study protocol.

BACKGROUND: Accelerated partial breast irradiation (APBI) is a treatment option for selected early stage breast cancer patients. Some APBI techniques lead to skin toxicity with the skin dose as main risk factor. We hypothesize that a spacer injected between the skin and target volume reduces the skin dose and subsequent toxicity in permanent breast seed implant (PBSI) patients. METHODS: In this parallel-group, single-center, randomized controlled trial, the effect of a subcutaneous spacer injection on skin toxicity among patients treated with PBSI is tested. Eligibility for participation is derived from international guidelines for suitable patients for partial breast radiotherapy, e.g. women aged ≥ 50 years with a histologically proven non-lobular breast carcinoma and/or ductal carcinoma in situ (DCIS), tumor size ≤ 3 cm, node-negative, and PBSI technically feasible. Among exclusion criteria are neoadjuvant chemotherapy, lymphovascular invasion, and allergy for hyaluronic acid. For the patients allocated to receive spacer, after the PBSI procedure, 4-10 cc of biodegradable hyaluronic acid (Barrigel™, Palette Life Sciences, Santa Barbara, CA, USA or Restylane SubQ®, Galderma Benelux, Breda, the Netherlands) is injected directly under the skin using ultrasound guidance to create an extra 0.5-1 cm space between the treatment volume and the skin. The primary outcome is the rate of telangiectasia at two years, blindly assessed using Bentzen's 4-point scale. Secondary outcomes include: local recurrence; disease-free and overall survival rates; adverse events (pain, redness, skin/subcutaneous induration, radiation dermatitis, pigmentation, surgical site infection); skin dose; cosmetic and functional results; and health-related quality of life. A Fisher's exact test will be used to test differences between groups on the primary outcome. Previous studies found 22.4% telangiectasia at two years. We expect the use of a spacer could reduce the occurrence of telangiectasia to 7.7%. A sample size of 230 patients will allow for a 10% lost to follow-up rate. DISCUSSION: In this study, the effect of a subcutaneous spacer injection on the skin dose, late skin toxicity, and cosmetic outcome is tested in patients treated with PBSI in the setting of breast-conserving therapy. Our results will be relevant for most forms of breast brachytherapy as well as robotic radiosurgery, as skin spacers could protect the skin with these other techniques. TRIAL REGISTRATION: Netherlands Trial Register, NTR6549 . Registered on 27 June 2017.

Development and psychometric evaluation of a Dutch-translated shorter Breast Cancer Treatment Outcome Scale (Dutch BCTOS-13).

PURPOSE: To create a Dutch translated short version of the Breast Cancer Treatment Outcome Scale (BCTOS) and validate it in patients who have completed both breast conserving surgery and adjuvant radiotherapy. METHODS: The BCTOS consists of items comparing the treated with the untreated breast. After forward and backward translation, we tested the BCTOS-12 plus 5 additional items. Two-hundred breast cancer patients treated with breast conserving therapy (BCT) between January 2016 and December 2017, were asked to complete the BCTOS items twice with a 2 week interval. The EORTC QLQ-BR23 breast and arm symptoms subscales were completed once in parallel. Feasibility was assessed by missing or non-unique answer rates and content validity with floor and ceiling effect analysis. Construct validity was evaluated with 1) principal component analysis (PCA) 2) convergent validity and 3) known groups comparison (clinical validity differentiating between patients with and without locoregional side effects). From all potential items with good feasibility, content and construct validity, items were selected for the Dutch BCTOS based on clinical validity. The relation to the EORTC QLQ-BR23 subscales and reliability was tested for the new Dutch BCTOS. RESULTS: Hundred and one of 200 (50.5%) approached patients participated in this study, with follow-up after surgery ranging from 5 to 29 months. Feasibility was high (1.5% missing answers). Content validity testing showed a floor effect > 20% in all 17 items. PCA showed that all items loaded well (> 0.4) into the assigned subscale and revealed two distinct subscales: cosmesis and function. Based on clinical validity, item "breast shape" was replaced by "breast elevation/position" and "overall skin appearance". Very good clinical validity (Cohen's d = 1.38) was found for the new Dutch BCTOS-13. Correlation to the EORTC QLQ-BR23 subscales was high (ICC = 0.65-0.85) for both subscales. Test-retest reliability (Cohen's d = 0.105) and internal consistency (Cronbach's α =0.90) were excellent. CONCLUSIONS: Psychometric evaluation of a newly developed Dutch BCTOS-13 questionnaire in BCT patients showed excellent results, that were slightly better than the original BCTOS-22 and the shortened BCTOS-12. The good clinical validity makes the BCTOS-13 a useful tool to identify patients with unfavourable cosmetic and functional outcomes, requiring specific attention.

A randomized controlled trial on the effect of a silver carboxymethylcellulose dressing on surgical site infections after breast cancer surgery.

BACKGROUND: The incidence of surgical site infections (SSIs) after breast cancer surgery is relatively high; ranging from 3 to 19%. The role of wound dressings in the prevention of SSI after breast cancer surgery is unclear. This study compares a silver carboxymethylcellulose dressing (AQUACEL Ag Surgical (Aquacel) with standard wound dressing in SSI rate after breast cancer surgery. PATIENTS AND METHODS: A single-centre randomized controlled trial among women ≥18 years, diagnosed with breast cancer, undergoing breast conserving or ablative surgery, was conducted in a combined in and outpatient setting. The intervention was the use of Aquacel, compared with standard gauze dressing. Primary outcome measure was SSI following CDC criteria. RESULTS: A total of 230 patients were analysed: 106 in the Aquacel group and 124 controls. Seven patients (6.6%) developed SSI in the Aquacel group and 16 patients (12.9%) in the control group (RR 0.51 [95% Confidence Interval (CI): 0.22-1.20]; p = 0.112; adjusted OR 0.49 [0.19-1.25] p = 0.135)). Unplanned exploratory subgroup analysis of breast conserving surgery patients showed that SSI rate was 1/56 (1.8%) in the Aquacel group vs. 7/65 (10.8%) in controls; adjusted OR 0.15 [0.02-1.31] p = 0.087. The Aquacel group showed better patient satisfaction (median 8 vs. 7 on a Numerical Rating Scale, p = 0.006), fewer dressing changes within 48 hours(adjusted OR 0.12 [0.05-0.27] p<0.001), fewer re-operations (0% vs. 3.2%, p = 0.062), and lower mean wound-related treatment costs, both in a high (€265.42 (SD = 908) vs. €470.65 (SD = 1223) [p<0.001]) and low (€59.12 (SD = 129) vs. €67.55 (SD = 172) [p<0.001]) attributable costs of SSI model. CONCLUSION: In this randomized controlled trial in women undergoing surgery for breast cancer, the use of AQUACEL Ag Surgical wound dressing did not significantly reduce the occurrence of SSIs compared to standard gauze dressing. The use of Aquacel resulted in significantly improved patient satisfaction, reduced dressing changes and reduced wound-related costs. TRIAL REGISTRATION: www.trialregister.nl: NTR5840.