Clinical trial NCT02466737: Comparison of Axillary Sentinel Lymph Node Biopsy Versus no Axillary Surgery
Official title: Comparison of Axillary Sentinel Lymph Node Biopsy Versus no Axillary Surgery in Patients With Early-stage Invasive Breast Cancer and Breast-conserving Surgery: a Randomized Prospective Surgical Trial. Intergroup-Sentinel-Mamma (INSEMA)-Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Breast Cancer
Keywords: axillary surgery
sentinel lymph node biopsy
Lead sponsor: University of Rostock
Sponsor class: OTHER
Collaborators: name: German Cancer Aid
name: GBG Forschungs GmbH
First posted: 2015-06-09
Enrollment: 5505
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Although there is no doubt that the presence of lymph node metastases worsens prognosis of a patient, unambiguous evidence to support lymph node dissection is still lacking. For many solid tumors, the role of lymph node dissection is yet controversial, and may depend on the tumor type and the stage of patient presentation for diagnosis. Axillary surgery for breast cancer is now considered as staging procedure that does not seem to influence breast cancer mortality. Women with breast cancer have benefitted greatly from a series of carefully performed randomized controlled trial focusing on axillary surgery. The objective of INSEMA is to show that less axillary surgery is better, in that oncological outcomes are the same and less surgical intervention will result in fewer surgical complications.

Detailed description: Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary (seed-and-soil model). Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement.

The goal of the present study is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding disease-free survival outcome compared with the standard arm. All patients will be first randomized to either no axillary surgical intervention or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than four involved nodes (1-3 macrometastases). Patients with four or more metastatic sentinel lymph nodes should undergo completion ALND.

Postoperative systemic treatment should be based on local multidisciplinary tumor board recommendation according to the current German AGO and S3 guidelines. For women who are treated with breast-conserving surgery, the most common site of local recurrence is the conserved ipsilateral breast itself. Thus, whole-breast radiation therapy after breast-conserving surgery is mandatory and should be performed according to the current guidelines (S3, AGO, DEGRO).

During follow-up, patients will be assessed for disease recurrence according to standard clinical practice. History and physical examination will be performed every 6 months for the first 36 months and yearly thereafter. Annual mammography and sonography will be required; other testing will be based on symptoms and investigator preference. The total number of patients to be randomized into the trial will be approximately 7,095. An event-driven final efficacy analysis will be performed per-protocol for two primary objectives.

Eligibility criteria: Inclusion Criteria:

* Written informed consent prior to beginning breast-conserving surgery, including expected cooperation of the patients for follow-up, must be obtained and documented according to the local regulatory requirements
* Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy or open biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery is planned
* Age at diagnosis at least 18 years
* Preoperative imaging techniques with estimated tumor size of \<5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status)
* Clinically and sonographically tumor-free axilla prior to core biopsy (cN0/iN0)
* In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration (FNA) biopsy of the sonographically suspected lymph node is required before randomization
* No clinical evidence for distant metastasis (M0)
* Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation)

Exclusion Criteria:

* History of malignancy within last 5 years, except curatively treated basalioma of the skin and carcinoma in situ of the cervix
* Time since core biopsy \>3 months (optimal \<1 month)
* Previous and already (neoadjuvant) treated invasive breast carcinoma
* Histologically non-invasive breast carcinoma
* cT3/T4 or iT3/T4 tumors
* pregnant or lactating patients
* Planned total mastectomy (e.g. multicentric tumors )
* Planned intraoperative radiotherapy (e.g. Intrabeam) or postoperative partial breast irradiation (e.g. multicatheter technique) alone; both procedures are allowed as boost techniques
* Male patients

Primary outcomes:
measure: invasive disease-free survival (IDFS) after breast-conserving surgery
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Dornbirn
country: Austria
facility: BGZ Dornbirn, Gynäkologie
city: Graz
country: Austria
facility: LKH Uni-Klinikum Graz, Gynäkologie
city: Linz
country: Austria
facility: Ordensklinikum-BHS
city: Linz
country: Austria
facility: Kepler Universitätsklinikum
city: Salzburg
country: Austria
facility: Universitätsfrauenklinik Salzburg
city: St. Veit/Glan
country: Austria
facility: KH der Barmherzigen Brüder
city: Wien
country: Austria
facility: Hanusch-Krankenhaus, Brustzentrum
city: Wolfsberg
country: Austria
facility: Landes-Krankenhaus Wolfsberg, Chirurgie
city: Brandenburg
country: Germany
facility: Städtisches Klinikum Brandenburg
state: BB
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum
state: BB
city: Ludwigsfelde
country: Germany
facility: Ev. Krankenhaus, Frauenklinik
state: BB
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann
state: BB
city: Berlin-Buch
country: Germany
facility: Helios Klinikum, Klinik für Gynäkologie
state: BE
city: Berlin
country: Germany
facility: Charite Campus Mitte
state: BE
city: Berlin
country: Germany
facility: Sana Klinikum Berlin-Lichtenberg
state: BE
city: Berlin
country: Germany
facility: St. Gertrauden Krankenhaus
state: BE
city: Berlin
country: Germany
facility: DRK Kliniken Köpenick
state: BE
city: Berlin
country: Germany
facility: Park-Klinik Weißensee
state: BE
city: Berlin
country: Germany
facility: Evang. Waldkrankenhaus Spandau
state: BE
city: Berlin
country: Germany
facility: DRK-Kliniken Westend
state: BE
city: Berlin
country: Germany
facility: Krankenhaus Waldfriede
state: BE
city: Aalen
country: Germany
facility: Ostalb-Klinikum, Brustzentrum Aalen
state: BW
city: Bad Mergentheim
country: Germany
facility: Caritas-Krankenhaus Brustzentrum Tauberfranken
state: BW
city: Baden-Baden
country: Germany
facility: Klinikum Mittelbach Brustzentrum
state: BW
city: Biberach
country: Germany
facility: Sana-Klinikum Biberach
state: BW
city: Bietigheim
country: Germany
facility: Krankenhaus Bietigheim
state: BW
city: Bruchsal
country: Germany
facility: Fürst-Stirum-Klinik
state: BW
city: Böblingen
country: Germany
facility: Klinikum Böblingen
state: BW
city: Ehingen
country: Germany
facility: Brustzentrum Donau-Riß
state: BW
city: Esslingen
country: Germany
facility: Klinikum Esslingen
state: BW
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
state: BW
city: Freudenstadt
country: Germany
facility: Frauenklinik Freudenstadt
state: BW
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: BW
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
state: BW
city: Karlsruhe
country: Germany
facility: ViDia Christliche Kliniken, Diakonissenkrankenhaus Karlsruhe
state: BW
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
state: BW
city: Lörrach
country: Germany
facility: St. Elisabethen Krankenhaus
state: BW
city: Pforzheim
country: Germany
facility: Helios Klinik Pforzheim
state: BW
city: Pforzheim
country: Germany
facility: Siloah St. Trudpert Klinikum
state: BW
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg
state: BW
city: Rottweil
country: Germany
facility: Helios Klinik Rottweil
state: BW
city: Schorndorf
country: Germany
facility: Rems-Murr Klinik
state: BW
city: Tuttlingen
country: Germany
facility: Klinikum Tuttlingen
state: BW
city: Tübingen
country: Germany
facility: Universitätsfrauenklinik
state: BW
city: Ulm
country: Germany
facility: Universitätsfrauenklinik Ulm
state: BW
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald-Baar Klinikum
state: BW
city: Winnenden
country: Germany
facility: Rems-Murr Kliniken
state: BW
city: Amberg
country: Germany
facility: Klinikum St. Marien
state: BY
city: Ansbach
country: Germany
facility: AN regiomed Klinikum Ansbach
state: BY
city: Aschaffenburg
country: Germany
facility: Klinikum Aschaffenburg
state: BY
city: Augsburg
country: Germany
facility: Hämatologisch-onkologische Praxis
state: BY
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth GmbH, Frauenklinik
state: BY
city: Ebersberg
country: Germany
facility: Kreisklinik Ebersberg
state: BY
city: Eggenfelden
country: Germany
facility: Gynäkologische Praxis
state: BY
city: Fürth
country: Germany
facility: Klinikum Fürth
state: BY
city: Kempten
country: Germany
facility: Klinikum Kempten-Oberallgäu
state: BY
city: Landshut
country: Germany
facility: Klinikum Landshut
state: BY
city: Marktredwitz
country: Germany
facility: Klinikum Fichtelgebirge gGmbH, Brustzentrum
state: BY
city: Memmingen
country: Germany
facility: Klinikum Memmingen
state: BY
city: München
country: Germany
facility: Klinikum der Universität München
state: BY
city: München
country: Germany
facility: Klinikum Harlaching, Frauenklinik
state: BY
city: Passau
country: Germany
facility: Klinikum Passau
state: BY
city: Regensburg
country: Germany
facility: Frauenklinik der Universität Regensburg, Caritas-Krankenhaus St. Josef
state: BY
city: Starnberg
country: Germany
facility: Klinikum Starnberg
state: BY
city: Traunstein
country: Germany
facility: Klinikum Traunstein
state: BY
city: Weiden
country: Germany
facility: Kliniken Nordoberpfalz AG, Brustzentrum Weiden
state: BY
city: Würzburg
country: Germany
facility: Rotkreuzklinik Würzburg
state: BY
city: Würzburg
country: Germany
facility: Klinikum Mitte, Missio Brustzentrum
state: BY
city: Bremen
country: Germany
facility: St. Joseph Stift
state: HB
city: Bremen
country: Germany
facility: DIAKO Krankenhaus Bremen
state: HB
city: Frankfurt am Main
country: Germany
facility: Klinikum Frankfurt Höchst
state: HE
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
state: HE
city: Frankfurt
country: Germany
facility: Universitätsklinikum Brustzentrum
state: HE
city: Gelnhausen
country: Germany
facility: Main-Kinzig-Kliniken Gelnhausen
state: HE
city: Hanau
country: Germany
facility: Klinikum Hanau GmbH
state: HE
city: Heppenheim
country: Germany
facility: Kreiskrankenhaus Bergstraße gGmbH
state: HE
city: Kassel
country: Germany
facility: Elisabeth Krankenhaus Kassel
state: HE
city: Kassel
country: Germany
facility: Klinikum Kassel
state: HE
city: Offenbach
country: Germany
facility: Sana Klinikum Offenbach
state: HE
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital, Frauenklinik
state: HE
city: Wiesbaden
country: Germany
facility: Asklepios Paulinenklinik
state: HE
city: Wiesbaden
country: Germany
facility: Helios Dr. Horst Schmidt Klinikum
state: HE
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg, Brustzentrum
state: HH
city: Hamburg
country: Germany
facility: Agaplesion Diakonieklinikum, Brustzentrum
state: HH
city: Hamburg
country: Germany
facility: Gynäkologische Praxisklinik Harburg
state: HH
city: Hamburg
country: Germany
facility: Albertinen-Krankenhaus, Brustzentrum
state: HH
city: Greifswald
country: Germany
facility: Universität Greifswald, Frauenklinik
state: MV
city: Neubrandenburg
country: Germany
facility: Dietrich Bonhoeffer Klinikum, Brustzentrum
state: MV
city: Rostock
country: Germany
facility: Universitäts-Frauenklinik
state: MV
city: Schwerin
country: Germany
facility: Helios Kliniken Schwerin
state: MV
city: Celle
country: Germany
facility: AKH Celle, Brustzentrum
state: NI
city: Georgsmarienhütte
country: Germany
facility: Franziskus Hospital Harderberg
state: NI
city: Gifhorn
country: Germany
facility: Helios Klinikum Gifhorn
state: NI
city: Hannover
country: Germany
facility: Henriettenstiftung Frauenklinik
state: NI
city: Hannover
country: Germany
facility: Vinzenzkrankenhaus Hannover
state: NI
city: Hannover
country: Germany
facility: MHH Frauenklinik
state: NI
city: Hildesheim
country: Germany
facility: St. Bernward Krankenhaus
state: NI
city: Lingen
country: Germany
facility: Bonifatius-Hospital, Brustzentrum
state: NI
city: Nordhorn
country: Germany
facility: Euregio-Klinik Brustzentrum Nordhorn
state: NI
city: Obernkirchen
country: Germany
facility: Agaplesion Ev. Klinikum, Brustzentrum Schaumburg
state: NI
city: Osnabrück
country: Germany
facility: Klinikum Osnabrück
state: NI
city: Rotenburg
country: Germany
facility: Diakoniekrankenhaus, Frauenklinik
state: NI
city: Wolfsburg
country: Germany
facility: Klinikum Wolfsburg, Frauenklinik
state: NI
city: Bochum
country: Germany
facility: Augusta-Klinik
state: Nordrhein
city: Bonn
country: Germany
facility: Universitätsfrauenklinik Bonn
state: Nordrhein
city: Bottrop
country: Germany
facility: Marienhospital Bottrop
state: Nordrhein
city: Düsseldorf
country: Germany
facility: Frauenklinik der H.-Heine-Universität
state: Nordrhein
city: Essen
country: Germany
facility: Universitätsklinikum Essen Frauenklinik
state: Nordrhein
city: Essen
country: Germany
facility: Kliniken Essen-Mitte
state: Nordrhein
city: Köln
country: Germany
facility: Uniklinik Köln
state: Nordrhein
city: Köln
country: Germany
facility: St. Elisabeth Krankenhaus, Brustzentrum
state: Nordrhein
city: Lüdenscheid
country: Germany
facility: Klinikum Märkische Kliniken, Brustzentrum
state: Nordrhein
city: Lünen
country: Germany
facility: Klinikum Lünen, Brustzentrum
state: Nordrhein
city: Münster
country: Germany
facility: St. Franziskus-Hospital
state: Nordrhein
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein
city: Schwerte
country: Germany
facility: Marienkrankenhaus
state: Nordrhein
city: Siegen
country: Germany
facility: St. Marienkrankenhaus, Frauenklinik
state: Nordrhein
city: Troisdorf
country: Germany
facility: St. Josef-Hospital, BZ Rhein-Sieg
state: Nordrhein
city: Unna
country: Germany
facility: Katharinen-Hospital, Brustzentrum
state: Nordrhein
city: Wesel
country: Germany
facility: Marien-Hospital
state: Nordrhein
city: Kaiserslautern
country: Germany
facility: Westpfalz Klinikum
state: RP
city: Koblenz
country: Germany
facility: BZ Mittelrhein Koblenz+Mayen
state: RP
city: Ludwigshafen
country: Germany
facility: Klinikum Ludwigshafen
state: RP
city: Speyer
country: Germany
facility: Diakonissen-Stiftungs-Krankenhaus Speyer
state: RP
city: Worms
country: Germany
facility: Stadtkrankenhaus Worms
state: RP
city: Halle/Saale
country: Germany
facility: Universität Halle/Saale, Frauenklinik
state: Saint
city: Halle
country: Germany
facility: Krankenhaus St. Elisabeth und St. Barbara
state: Saint
city: Magdeburg
country: Germany
facility: Klinik St. Marienstift
state: Saint
city: Salzwedel
country: Germany
facility: Altmark-Klinikum Brustzentrum
state: Saint
city: Stendal
country: Germany
facility: Johanniter-Krankenhaus, Frauenklinik
state: Saint
city: Wernigerode
country: Germany
facility: Harzklinikum, Brustzentrum Harz
state: Saint
city: Eutin
country: Germany
facility: Sana-Klinik
state: SH
city: Flensburg
country: Germany
facility: DIAKO Diakonissenkrankenhaus
state: SH
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Hostein
state: SH
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Lübeck
state: SH
city: Borna
country: Germany
facility: Brustzentrum Nordsachsen
state: SN
city: Dresden
country: Germany
facility: Diakonissenkrankenhaus
state: SN
city: Dresden
country: Germany
facility: Krankenhaus St. Joseph-Stift
state: SN
city: Dresden
country: Germany
facility: Universität Dresden, Frauenklinik
state: SN
city: Görlitz
country: Germany
facility: Städtisches Klinikum
state: SN
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Brustzentrum
state: SN
city: Leipzig
country: Germany
facility: St. Elisabeth Krankenhaus
state: SN
city: Rodewisch
country: Germany
facility: Klinikum Obergöltzsch Rodewisch
state: SN
city: Schkeuditz
country: Germany
facility: Helios Klinik
state: SN
city: Bad Langensalza
country: Germany
facility: Hufeland-Klinik Bad Langensalza
state: TH
city: Gera
country: Germany
facility: SRH Waldklinikum
state: TH
city: Jena
country: Germany
facility: Universitätsklinikum Jena
state: TH
city: Meiningen
country: Germany
facility: Helios Klinikum Meiningen, Brustzentrum
state: TH
city: Suhl
country: Germany
facility: SRH Zentralklinikum Suhl
state: TH
city: Sömmerda
country: Germany
facility: DRK Krankenhaus, Brustzentrum
state: TH
Study officials:
affiliation: University Medicine Rostock
name: Toralf Reimer, MD, PhD
role: STUDY_CHAIR
References:
citation: Reimer T, Stachs A, Nekljudova V, Loibl S, Hartmann S, Wolter K, Hildebrandt G, Gerber B. Restricted Axillary Staging in Clinically and Sonographically Node-Negative Early Invasive Breast Cancer (c/iT1-2) in the Context of Breast Conserving Therapy: First Results Following Commencement of the Intergroup-Sentinel-Mamma (INSEMA) Trial. Geburtshilfe Frauenheilkd. 2017 Feb;77(2):149-157. doi: 10.1055/s-0042-122853.
citation: Hildebrandt G, Stachs A, Gerber B, Potenberg J, Krug D, Wolter K, Kuhn T, Zierhut D, Sedlmayer F, Kaiser J, Reitsamer R, Heil J, Nekljudova V, Bekes I, Loibl S, Reimer T. Central Review of Radiation Therapy Planning Among Patients with Breast-Conserving Surgery: Results from a Quality Assurance Process Integrated into the INSEMA Trial. Int J Radiat Oncol Biol Phys. 2020 Jul 15;107(4):683-693. doi: 10.1016/j.ijrobp.2020.04.042. Epub 2020 May 11.
citation: Reimer T, Stachs A, Veselinovic K, Polata S, Muller T, Kuhn T, Heil J, Ataseven B, Reitsamer R, Hildebrandt G, Knauer M, Golatta M, Stefek A, Zahm DM, Thill M, Nekljudova V, Krug D, Loibl S, Gerber B; INSEMA investigators. Patient-reported outcomes for the Intergroup Sentinel Mamma study (INSEMA): A randomised trial with persistent impact of axillary surgery on arm and breast symptoms in patients with early breast cancer. EClinicalMedicine. 2022 Nov 25;55:101756. doi: 10.1016/j.eclinm.2022.101756. eCollection 2023 Jan.
citation: Marme F, Krieghoff-Henning E, Gerber B, Schmitt M, Zahm DM, Bauerschlag D, Forstbauer H, Hildebrandt G, Ataseven B, Brodkorb T, Denkert C, Stachs A, Krug D, Heil J, Golatta M, Kuhn T, Nekljudova V, Gaiser T, Schonmehl R, Brochhausen C, Loibl S, Reimer T, Brinker TJ. Deep learning to predict breast cancer sentinel lymph node status on INSEMA histological images. Eur J Cancer. 2023 Dec;195:113390. doi: 10.1016/j.ejca.2023.113390. Epub 2023 Oct 18.
citation: Reimer T, Stachs A, Veselinovic K, Kuhn T, Heil J, Polata S, Marme F, Muller T, Hildebrandt G, Krug D, Ataseven B, Reitsamer R, Ruth S, Denkert C, Bekes I, Zahm DM, Thill M, Golatta M, Holtschmidt J, Knauer M, Nekljudova V, Loibl S, Gerber B. Axillary Surgery in Breast Cancer - Primary Results of the INSEMA Trial. N Engl J Med. 2025 Mar 13;392(11):1051-1064. doi: 10.1056/NEJMoa2412063. Epub 2024 Dec 12.