J.A. van der Hage

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)

BACKGROUND Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

First experiences of photoacoustic imaging for detection of melanoma metastases in resected human lymph nodes.

Excision and histological assessment of the first draining node (sentinel lymph node) is a frequently used method to assess metastatic lymph node involvement related to cutaneous melanoma. Due to the time required for accurate histological assessment, nodal status is not immediately available to the surgeon. Hence, in case histological examination shows metastases, the patient has to be recalled to perform additional lymphadenectomy. To overcome these drawbacks we studied the applicability of photoacoustic tomographic imaging as an intra‐operative modality for examining the status of resected lymph nodes.

Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer

INTRODUCTION Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval. METHOD Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival. RESULTS In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10 years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p ≤ 0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001). CONCLUSION This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease.

Complete resection of recurrent and initially unresectable dermatofibrosarcoma protuberans downsized by Imatinib

Curative surgical treatment of recurrent, locally advanced dermatofibrosarcoma protuberans is often limited owing to a close relation of the tumor with important anatomical structures. Targeted therapy with imatinib, a tyrosine kinase inhibitor, may cause significant reduction of tumor volume, thereby enabling radical surgery. This treatment strategy, therefore, offers a chance of cure for selected patients with advanced dermatofibrosarcoma protuberans. In addition, preoperative treatment with imatinib may decrease possible disfigurement related to radical surgery for large tumors.

Feasibility of magnetic marker localisation for non-palpable breast cancer

OBJECTIVES Accurate tumour localisation is essential for breast-conserving surgery of non-palpable tumours. Current localisation technologies are associated with disadvantages such as logistical challenges and migration issues (wire guided localisation) or legislative complexities and high administrative burden (radioactive localisation). We present MAgnetic MArker LOCalisation (MaMaLoc), a novel technology that aims to overcome these disadvantages using a magnetic marker and a magnetic detection probe. This feasibility study reports on the first experience with this new technology for breast cancer localisation. MATERIALS AND METHODS Fifteen patients with unifocal, non-palpable breast cancer were recruited. They received concurrent placement of the magnetic marker in addition to a radioactive iodine seed, which is standard of care in our clinic. In a subset of five patients, migration of the magnetic marker was studied. During surgery, a magnetic probe and gammaprobe were alternately used to localise the markers and guide surgery. The primary outcome parameter was successful transcutaneous identification of the magnetic marker. Additionally, data on radiologist and surgeon satisfaction were collected. RESULTS Magnetic marker placement was successful in all cases. Radiologists could easily adapt to the technology in the clinical workflow. Migration of the magnetic marker was negligible. The primary endpoint of the study was met with an identification rate of 100%. Both radiologists and surgeons reflected that the technology was intuitive to use and that it was comparable to radioactive iodine seed localisation. CONCLUSION Magnetic marker localisation for non-palpable breast cancer is feasible and safe, and may be a viable non-radioactive alternative to current localisation technologies.

Abstract OT2-1-03: The Z11 design for breast cancer patients undergoing a mastectomy

Background: The diagnostic work-up and treatment of axillary lymph nodes in breast cancer patients is an ongoing topic of research. The ACOSOG-Z0011 study demonstrated no additional value of complementary axillary lymph node dissection (cALND) in case of limited axillary sentinel lymph node (SLN) metastases in breast cancer patients undergoing breast conserving therapy1. It is questionable whether these results can be applied to patients undergoing a mastectomy2. Trial design: A prospective non-inferiority randomized multicenter trial was designed. Breast cancer patients with cT1-2N0 disease treated with mastectomy and limited axillary SLN metastases will be randomized for follow-up versus complementary axillary treatment. To assess the Quality of Life and morbidity benefits of this experimental treatment, 3 validated questionnaires will be used: QLQ-C30, QLQ-BR 23 and Lymph-ICF3-5. Eligibility criteria: – Women with histological confirmed cT1-2 invasive unilateral breast carcinoma – Clinical node negative: no palpable nodes in physical examination and the axillary ultrasound without signs of lymph node metastases (cyto-/histology if indicated) – Sentinel lymph node biopsy must contain at least one and a maximum of 3 (micro)metastases – Neoadjuvant systemic therapy is allowed Specific aims: Primary endpoint is the axillary recurrence rate. The number of delayed axillary dissections will be registered. Secondary endpoints are distant-disease free survival, overall survival, local recurrence, morbidity and Quality of Life. Statistical methods: Based on 5-year axillary recurrence free survival rate, a failure rate of 0.98 among controls and a true failure rate of 0.96 for study subjects are considered acceptable. Overall, 1114 patients will be included to be able to reject the null hypothesis that the failure rate for experimental and control subjects is inferior by at least 5% (D = −5%) with probability of 0.8 and alpha of 5%. Present accrual and target accrual: This study is expected to start in late 2012 after approval by the Ethical Medical Committee. References 1. Giuliano, A.E., et al., Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA, 2011. 305(6): p. 569–75. 2. Morrow, M. and A.E. Giuliano, To cut is to cure: can we really apply Z11 in practice? Ann Surg Oncol, 2011. 18(9): p. 2413–5. 3. Aaronson, N.K., et al., The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst, 1993. 85(5): p. 365–76. 4. Sprangers, M.A., et al., The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol, 1996. 14(10): p. 2756–68. 5. Devoogdt, N., et al., Lymphoedema Functioning, Disability and Health questionnaire (Lymph-ICF): reliability and validity. Phys Ther, 2011. 91(6): p. 944–57. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-1-03.

Guidelines for time-to-event end point definitions in breast cancer trials: Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials). [Ann Oncol, 26, (2015), 873-879] doi: 10.1093/annonc/mdv106

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)† S. Gourgou-Bourgade1,2*, D. Cameron3, P. Poortmans4, B. Asselain5, D. Azria6, F. Cardoso7, R. A’Hern8, J. Bliss8, J. Bogaerts9, H. Bonnefoi10, E. Brain11, M. J. Cardoso7, B. Chibaudel12, R. Coleman13, T. Cufer14, L. Dal Lago15, F. Dalenc16, E. De Azambuja15, M. Debled10, S. Delaloge17, T. Filleron16, J. Gligorov18, M. Gutowski19, W. Jacot20, C. Kirkove21, G. MacGrogan10, S. Michiels22,23, I. Negreiros24, B. V. Offersen25, F. Penault Llorca26,27, G. Pruneri28,29, H. Roche16, N. S. Russell30, F. Schmitt31,32, V. Servent33, B. Thürlimann34, M. Untch35, J. A. van der Hage36, G. van Tienhoven37, H. Wildiers38,39, J. Yarnold40, F. Bonnetain41, S. Mathoulin-Pélissier42,43, C. Bellera42,43 & T. S. Dabakuyo-Yonli44 Biostatistic Unit, Montpellier Cancer Institute, Montpellier; Data Center for Cancer Clinical Trials, CTD-INCa, Montpellier, France; Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK; Department of Radiation Oncology, Institute Verbeeten, Tilburg, The Netherlands; Department of Biostatistics, Institut Curie, Paris; Department of Radiation Oncology, Montpellier Cancer Institute, Montpellier, France; Breast Cancer Unit, Champalimaud Cancer Center, Lisbon, Portugal; Institute of Cancer Research, London, UK; EORTC Data Center (European Organization of Research and Treatment of Cancer Statistics Department), Brussels, Belgium; Institut Bergonié, Comprehensive Cancer Centre, Bordeaux; Departments of Clinical Research and Medical Oncology, Institut Curie Hôpital René Huguenin, Saint-Cloud; Department of Medical Oncology, Hôpital Saint-Antoine, Paris, France; FRCP, FRCPE YCR National Institute for Health Research Cancer Research Network (NCRN), Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield Cancer Research Centre, Sheffield, UK; University Clinic Golnik, Golnik, Slovenia; Institut Jules Bordet, University ‘Libre’ of Brussels, Brussels, Belgium; Institut Claudius Régaud, Toulouse; Breast Cancer Group, Gustave Roussy Institute, Villejuif; APHP Tenon – University Cancer Institute – Pierre & Marie Curie, Sorbonne University, Paris; Departments of Surgery; Medical Oncology, Montpellier Cancer Institute, Montpellier, France; Université catholique Louvain, Louvain-la-Neuve, Belgium; Biostatistic and Epidemiology Unit, Gustave Roussy, Villejuif; University of Paris-Sud, Villejuif, France; Breast Unit, Hospital CUF Descobertas, Lisbon, Portugal; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark; Centre Jean Perrin, Clermont-Ferrand; ERTICA EA4677, UFR Medicine, University of Clermont-Ferrand 1, Clermont-Ferrand, France; European Institute of Oncology, Milan; University of Milan, School of Medicine, Milan, Italy; Department of Radiotherapy, The Netherlands Cancer Institute Antoni van Leeuwnhoek Hospital, Amsterdam, The Netherlands; IPATIMUP (Institute of Molecular Pathology and Immunology of the University of Porto), Porto; Medical Faculty of Porto University, Porto, Portugal; Oscar Lambret Comprehensive Cancer Center, Lille, France; Kantonsspital St Gallen, Breast Center, St Gallen, Switzerland; Clinic for Gynecology, Gynecologic Oncology and Obstetrics—Interdisciplinary Breast Cancer Center, HELIOS Klinikum Berlin-Buch, Berlin, Germany; Department of Surgical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam; Academic Medical Center Amsterdam, Amsterdam, The Netherlands; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven; Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, Leuven, Belgium; The Institute of Cancer Research, Royal Cancer Hospital, London, UK; Methodological and Quality of Life Unit in Oncology (EA3181), CHU Besançon, Besançon; Clinical and Epidemiological Research Unit, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux; Clinical Epidemiology Unit, INSERM CIC 14.01 (Clinical Epidemiology), Bordeaux; Biostatistics and Quality of Life Unit (EA4184), Centre Georges François Leclerc Comprehensive Cancer Centre, Dijon, France

The management of soft tissue tumours of the abdominal wall

BACKGROUND Soft tissue tumours of the abdominal wall account for approximately 10% of all soft tissue tumours. Tumours at this site comprise a heterogeneous group of pathologies with distinct clinical behaviours and responses to treatment. The management of these tumours has largely been extrapolated from studies of soft tissue tumours at other sites. This review aims to summarise the existing data relating to abdominal wall tumours and suggest principles for managing soft tissue tumours at this site. METHODS Relevant articles were retrieved from a comprehensive literature search using the PubMed database. Key words included abdominal wall, soft tissue tumours, surgery, radiotherapy and chemotherapy. No restrictions on publication date were used. RESULTS The most common pathologies presenting in the abdominal wall are desmoid tumours, soft-tissue sarcoma and dermatofibrosarcoma protuberans (DFSP). Desmoid tumours should be managed with an initial period of observation, with surgery reserved for progressive lesions. Surgery should be the primary treatment for soft-tissue sarcomas and DFSP, with radiotherapy reserved for large-high grade tumours and preferentially given pre-operatively. CONCLUSIONS Abdominal wall tumours are rare and should be managed in centres with experience in the management of soft tissue tumours. Management should be tailored to the biological behaviour of specific pathologies.