Thijs van Dalen

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

BACKGROUND If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING EORTC Charitable Trust.

Randomized clinical trial of LigaSure versus conventional suture ligation in thyroid surgery.

BackgroundIn thyroid surgery vessel division and haemostasis make up an important and time consuming part of the operation. While the presence of the recurrent laryngeal nerve limits the liberal use of diathermia, the many arterial and venous branches to and from the thyroid gland necessitates the use of numerous conventional suture ligatures.This study evaluates the effect of using a vessel sealing system on operation time during thyroid surgery.MethodsA randomized clinical trial was performed between September 2005 and October 2008 in a teaching hospital. Forty patients undergoing total hemithyroidectomy participated in the trial. Twenty were randomized to the intraoperative use of the LigaSure Precise™ vessel sealing system, and twenty to the use of conventional suture ligatures.ResultsThe total median operation time was 10 minutes shorter in the LigaSure group (56 versus 66 minutes, P = 0.001). No significant differences in complications were noticed.ConclusionUsing an electrothermal vessel sealing system during thyroid surgery is time saving.Trial registrationThis trial was registered in the international standard randomized controlled trials number register (ISRCTNR) under number ISRCTNR82389535.

Variation between hospitals in surgical margins after first breast-conserving surgery in the Netherlands

Surgical margin status after first breast-conserving surgery (BCS) is used as a quality indicator of breast cancer care in the Netherlands. The aim is to describe the variation in surgical margin status between hospitals. 7,345 patients with DCIS or invasive cancer (T1-2,N0-1,M0) diagnosed between July 1, 2008, and June 30, 2009, who underwent BCS as first surgery, were selected from the Netherlands Cancer Registry. Patients were treated in 96 hospitals. Maximum target values were 30% ‘focally positive’ or ‘more than focally positive’ for DCIS and 10% ‘more than focally positive’ for invasive carcinoma. Results per hospital are presented in funnel plots. For invasive carcinoma, multivariate logistic regression was used to adjust for case mix. Overall 28.5% (95% CI: 25.5–31.4%) of DCIS and 9.1% (95% CI: 8.4–9.8%) of invasive carcinoma had positive margins. Variation between hospitals was substantial. 6 and 10 hospitals, respectively, for DCIS and invasive cancer showed percentages above the upper limit of agreement. Case mix correction led to significant different conclusions for 5 hospitals. After case mix correction, 10 hospitals showed significant higher rates, while 7 hospitals showed significant lower rates. High rates were not related to breast cancer patient volume or type of hospital (teaching vs. non-teaching). Higher rates were related to hospitals where the policy is to aim for BCS instead of mastectomy. The overall percentage of positive margins in the Netherlands is within the predefined targets. The variation between hospitals is substantial but can be largely explained by coincidence. Case mix correction leads to relevant shifts.

Contemporary Locoregional Recurrence Rates in Young Patients With Early-Stage Breast Cancer

PURPOSE The aim of this study was to evaluate contemporary rates of local recurrence (LR) and regional recurrence (RR) in young patients with breast cancer in relation to tumor biology as expressed by biomarker subtypes. PATIENTS AND METHODS Women < 35 years of age who underwent surgery for primary unilateral invasive breast cancer between 2003 and 2008 were selected from the Netherlands Cancer Registry. Patients were categorized according to biomarker subtypes on the basis of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. The 5-year risks of developing LR and regional lymph node recurrence were estimated by using Kaplan-Meier statistics. RESULTS A total of 1,000 patients were identified, of whom 59% had a known subtype: 39% HR-positive/HER2-negative; 17% HR-positive/HER2-positive; 10% HR-negative/HER2-positive; and 34% HR-negative/HER2-negative (triple negative). Overall 5-year LR and RR rates were 3.5% and 3.7%, respectively. A decreasing trend for both rates was observed over time and was accompanied by a significant decrease in the risk of distant metastases (DM). LR occurred in 4.2%, RR in 6.1%, and DM in 17.8% of patients in 2003, and in 3.2%, 4.4%, and 10.0%, respectively, in 2008. LR and RR rates varied with biomarker subtype. These differences were borderline significant when analyzed for the entire study period (P = .056 and P = .014, respectively) and leveled off after the introduction of trastuzumab after 2005 (P = .24 and P = .42, respectively). Patients with lymph node metastases at the time of diagnosis had an increased risk of RR. The type of surgery performed-breast-conserving or mastectomy-did not influence rates of LR and RR. CONCLUSION Overall, the rates of LR and RR in young patients with early-stage breast cancer were relatively low and varied by biomarker subtype.

Long-term Results of a Randomized Double-blinded Prospective Trial of a Lightweight (Ultrapro) Versus a Heavyweight Mesh (Prolene) in Laparoscopic Total Extraperitoneal Inguinal Hernia Repair (TULP-trial).

Objective:The aim of the randomized clinical trial was to compare the 2 years of clinical outcomes of a lightweight (Ultrapro) vs a heavyweight (Prolene) mesh for laparoscopic total extraperitoneal (TEP) inguinal hernia repair. Background:Lightweight meshes reduce postoperative pain and stiffness in open anterior inguinal hernia repair. The discussion about a similar benefit for laparoscopic repair is ongoing, but concerns exist about higher recurrence rates. Methods:Between March 2010 and October 2012, male patients who presented with a primary, reducible unilateral inguinal hernia who underwent day-case TEP repair were eligible. Outcome parameters included chronic pain, recurrence, foreign body feeling, and quality of life scores. Results:During the study period, 950 patients were included. One year postoperatively the presence of relevant pain (Numeric Rating Score 4–10) was significantly higher in the lightweight mesh group (2.9%) compared with the heavyweight mesh group (0.7%) (P = 0.01), and after 2 years this difference remained significant (P = 0.03). There were 4 (0.8%) recurrent hernias in the heavyweight mesh group and 13 (2.7%) in the lightweight group (P = 0.03). No differences in foreign body feeling or quality of life scores were detected. Conclusions:In TEP hernia surgery, there was no benefit of lightweight over heavyweight meshes observed 2 years postoperatively.

Does rapid genetic counseling and testing in newly diagnosed breast cancer patients cause additional psychosocial distress? results from a randomized clinical trial

Purpose:Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT.Methods:Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits.Results:Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes.Conclusions:In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.Genet Med 18 2, 137–144.

Clinical auditing as an instrument for quality improvement in breast cancer care in the Netherlands: The national NABON Breast Cancer Audit

In 2011, the NABON Breast Cancer Audit (NBCA) was instituted as a nation‐wide audit to address quality of breast cancer care and guideline adherence in the Netherlands. The development of the NBCA and the results of 4 years of auditing are described.

Fluorine-18 fluorocholine PET-CT localizes hyperparathyroidism in patients with inconclusive conventional imaging : a multicenter study from the Netherlands

BackgroundSeveral reports have shown good performance of fluorine-18 fluorocholine (18F-FCH) PET-computed tomography (CT) for parathyroid localization, although overall evidence remains scarce. We collected data from three institutions in the Netherlands and investigated the performance of 18F-FCH PET-CT as a second-line imaging modality. Materials and methodsWe performed a retrospective review of all patients at least 18 years who underwent 18F-FCH PET-CT for biochemically proven hyperparathyroidism (HPT) and inconclusive ultrasound and sestamibi scintigraphy. Acquisition of PET images was performed 30 min after the administration of 2 MBq/kg 18F-FCH, together with a low-dose CT. ResultsPET-CT scans were performed in 33 (75%) women and 11 (25%) men with a mean age of 58.9 (range 31–80 years). Three patients had multiple endocrine neoplasia type 1, one patient had tertiary HPT because of Alport syndrome and the remaining patients had sporadic primary HPT. 18F-FCH PET-CT was positive in 34/44 (77.3%) cases. Of the 35 abnormal glands resected in 33 patients, 18F-FCH PET-CT could successfully localize 33/35 (94.3%), with only one false-positive result [positive predictive value (PPV)=97.1%]. Comparison of the 10 patients with negative PET-CT with the 34 patients with positive PET-CT showed no significant differences in age, sex, ratio of preoperative calcium, use of cinacalcet, history of neck surgery, and concomitant multinodular goiter. ConclusionOur study shows excellent performance of 18F-FCH PET-CT in patients with HPT and inconclusive conventional imaging. Because of its favorable characteristics with high performance, prospective studies should be initiated to determine whether this new technique may replace conventional sestamibi scintigraphy as a first-line imaging modality.

The additional value of intraoperative parathyroid hormone assessment is marginal in patients with nonfamilial primary hyperparathyroidism: a prospective cohort study.

BACKGROUND The success of minimally invasive parathyroidectomy is attributed to evolving preoperative imaging techniques and intraoperative parathyroid hormone (IOPTH) measurement. The additional value of IOPTH measurement in patients undergoing surgery for primary hyperparathyroidism (pHPT) was evaluated. METHODS Between 1999 and 2010 there were 119 patients who underwent surgery for pHPT at our institutions. In all patients, preoperative imaging was performed and IOPTH samples were collected prospectively but the results were not disclosed during surgery. RESULTS Postoperative calcium level normalized in 114 patients (96%). The 5 surgical failures represented the maximum yield of IOPTH sampling. Three of these patients would have been identified intraoperatively by an inadequate IOPTH decrease, whereas IOPTH decreased inaccurately in the other 2 patients. In addition, in 1 of these 3 patients no abnormal gland was found during minimally invasive parathyroidectomy and subsequent conventional neck exploration. Therefore, only 2 reoperations would have been prevented (1.7%). CONCLUSIONS IOPTH would have changed the outcome in 2 patients, increasing the biochemical cure rate from 96% to 98%. We believe that although it can be helpful in certain cases, it may not be necessary routinely in patients treated for pHPT.

The effect of ultrapro or prolene mesh on postoperative pain and well-being following endoscopic Totally Extraperitoneal (TEP) hernia repair (TULP): study protocol for a randomized controlled trial

BackgroundThe purpose of this study was to describe the rationale and design of a randomized controlled trial analyzing the effects of mesh type (Ultrapro versus Prolene mesh) on postoperative pain and well-being following an endoscopic Totally Extraperitoneal (TEP) repair for inguinal hernias (short: TULP trial).Methods and designThe TULP trial is a prospective, two arm, double blind, randomized controlled trial to assess chronic postoperative pain and quality of life following implantation of a lightweight (Ultrapro) and heavyweight (Prolene) mesh in endoscopic TEP hernia repair. The setting is a high-volume single center hospital, specializing in TEP hernia repair. All patients are operated on by one of four surgeons. Adult male patients (≥18 years of age) with primary, reducible, unilateral inguinal hernias and no contraindications for TEP repair are eligible for inclusion in the study. The primary outcome is substantial chronic postoperative pain, defined as moderate to severe pain persisting ≥ 3 months postoperatively (Numerical Rating Scale, NRS 4–10). Secondary endpoints are the individual development of pain until three years after the TEP procedure, the quality of life (QoL), recurrence rate, patient satisfaction and complications.DiscussionLarge prospective randomized controlled studies with a long follow-up evaluating the incidence of chronic postoperative pain following implantation of lightweight and heavyweight mesh in endoscopic (TEP) hernia repair are limited. By studying the presence of pain and quality of life, but also complications and recurrences in a large patient population, a complete efficiency and feasibility assessment of both mesh types in TEP hernia repair will be performed.Trial registrationThe TULP study is registered in the Dutch Trial Register (NTR2131)