Comparison of Axillary Sentinel Lymph Node Biopsy Versus no Axillary Surgery

NCT ID: NCT02466737

Last Updated: 2024-12-19

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 5505 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2025-06-30

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.

Conditions

Breast Cancer

Keywords

axillary surgery; sentinel lymph node biopsy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT

Study Groups

no axillary surgery

Group Type: EXPERIMENTAL

no axillary surgery versus SLNB

Intervention Type: PROCEDURE

in cases with newly diagnosed breast cancer and clinically negative axillary status

sentinel lymph node biopsy

standard arm in first randomization

Group Type: ACTIVE_COMPARATOR

no axillary surgery versus SLNB

Intervention Type: PROCEDURE

in cases with newly diagnosed breast cancer and clinically negative axillary status

sentinel lymph node biopsy alone

Group Type: EXPERIMENTAL

SLNB versus completion ALND

Intervention Type: PROCEDURE

in cases with 1-3 macrometastases in sentinel lymph nodes

completion axillary lymph node dissection

standard arm in second randomization

Group Type: ACTIVE_COMPARATOR

SLNB versus completion ALND

Intervention Type: PROCEDURE

in cases with 1-3 macrometastases in sentinel lymph nodes

Interventions

no axillary surgery versus SLNB

in cases with newly diagnosed breast cancer and clinically negative axillary status

Intervention Type: PROCEDURE

SLNB versus completion ALND

in cases with 1-3 macrometastases in sentinel lymph nodes

Intervention Type: PROCEDURE

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

German Cancer Aid

OTHER

Sponsor Role: collaborator

GBG Forschungs GmbH

OTHER

Sponsor Role: collaborator

University of Rostock

OTHER

Sponsor Role: lead

Responsible Party

Toralf Reimer, MD PhD

Prof. Dr. Toralf Reimer

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Toralf Reimer, MD, PhD

Role: STUDY_CHAIR

University Medicine Rostock

Locations

BGZ Dornbirn, Gynäkologie

Dornbirn, , Austria

LKH Uni-Klinikum Graz, Gynäkologie

Graz, , Austria

Ordensklinikum-BHS

Linz, , Austria

Kepler Universitätsklinikum

Linz, , Austria

KH der Barmherzigen Brüder

Saint Veit/Glan, , Austria

Universitätsfrauenklinik Salzburg

Salzburg, , Austria

Hanusch-Krankenhaus, Brustzentrum

Vienna, , Austria

Landes-Krankenhaus Wolfsberg, Chirurgie

Wolfsberg, , Austria

Ostalb-Klinikum, Brustzentrum Aalen

Aalen, Baden-Wurttemberg, Germany

Caritas-Krankenhaus Brustzentrum Tauberfranken

Bad Mergentheim, Baden-Wurttemberg, Germany

Klinikum Mittelbach Brustzentrum

Baden-Baden, Baden-Wurttemberg, Germany

Sana-Klinikum Biberach

Biberach, Baden-Wurttemberg, Germany

Krankenhaus Bietigheim

Bietigheim, Baden-Wurttemberg, Germany

Klinikum Böblingen

Böblingen, Baden-Wurttemberg, Germany

Fürst-Stirum-Klinik

Bruchsal, Baden-Wurttemberg, Germany

Brustzentrum Donau-Riß

Ehingen, Baden-Wurttemberg, Germany

Klinikum Esslingen

Esslingen am Neckar, Baden-Wurttemberg, Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Frauenklinik Freudenstadt

Freudenstadt, Baden-Wurttemberg, Germany

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, Germany

Städtisches Klinikum Karlsruhe

Karlsruhe, Baden-Wurttemberg, Germany

ViDia Christliche Kliniken, Diakonissenkrankenhaus Karlsruhe

Karlsruhe, Baden-Wurttemberg, Germany

St. Elisabethen Krankenhaus

Loerrach, Baden-Wurttemberg, Germany

Klinikum Ludwigsburg

Ludwigsburg, Baden-Wurttemberg, Germany

Helios Klinik Pforzheim

Pforzheim, Baden-Wurttemberg, Germany

Siloah St. Trudpert Klinikum

Pforzheim, Baden-Wurttemberg, Germany

Klinikum am Steinenberg

Reutlingen, Baden-Wurttemberg, Germany

Helios Klinik Rottweil

Rottweil, Baden-Wurttemberg, Germany

Rems-Murr Klinik

Schorndorf, Baden-Wurttemberg, Germany

Klinikum Tuttlingen

Tuttlingen, Baden-Wurttemberg, Germany

Universitätsfrauenklinik

Tübingen, Baden-Wurttemberg, Germany

Universitätsfrauenklinik Ulm

Ulm, Baden-Wurttemberg, Germany

Schwarzwald-Baar Klinikum

Villingen-Schwenningen, Baden-Wurttemberg, Germany

Rems-Murr Kliniken

Winnenden, Baden-Wurttemberg, Germany

Klinikum St. Marien

Amberg, Bavaria, Germany

AN regiomed Klinikum Ansbach

Ansbach, Bavaria, Germany

Klinikum Aschaffenburg

Aschaffenburg, Bavaria, Germany

Hämatologisch-onkologische Praxis

Augsburg, Bavaria, Germany

Klinikum Bayreuth GmbH, Frauenklinik

Bayreuth, Bavaria, Germany

Kreisklinik Ebersberg

Ebersberg, Bavaria, Germany

Gynäkologische Praxis

Eggenfelden, Bavaria, Germany

Klinikum Fürth

Fürth, Bavaria, Germany

Klinikum Kempten-Oberallgäu

Kempten (Allgäu), Bavaria, Germany

Klinikum Landshut

Landshut, Bavaria, Germany

Klinikum Fichtelgebirge gGmbH, Brustzentrum

Marktredwitz, Bavaria, Germany

Klinikum Memmingen

Memmingen, Bavaria, Germany

Klinikum der Universität München

München, Bavaria, Germany

Klinikum Harlaching, Frauenklinik

München, Bavaria, Germany

Klinikum Passau

Passau, Bavaria, Germany

Frauenklinik der Universität Regensburg, Caritas-Krankenhaus St. Josef

Regensburg, Bavaria, Germany

Klinikum Starnberg

Starnberg, Bavaria, Germany

Klinikum Traunstein

Traunstein, Bavaria, Germany

Kliniken Nordoberpfalz AG, Brustzentrum Weiden

Weiden, Bavaria, Germany

Rotkreuzklinik Würzburg

Würzburg, Bavaria, Germany

Klinikum Mitte, Missio Brustzentrum

Würzburg, Bavaria, Germany

Städtisches Klinikum Brandenburg

Brandenburg, Brandenburg, Germany

Carl-Thiem-Klinikum

Cottbus, Brandenburg, Germany

Ev. Krankenhaus, Frauenklinik

Ludwigsfelde, Brandenburg, Germany

Klinikum Ernst von Bergmann

Potsdam, Brandenburg, Germany

St. Joseph Stift

Bremen, City state Bremen, Germany

DIAKO Krankenhaus Bremen

Bremen, City state Bremen, Germany

Universitätsklinikum Hamburg, Brustzentrum

Hamburg, City state of Hamburg, Germany

Agaplesion Diakonieklinikum, Brustzentrum

Hamburg, City state of Hamburg, Germany

Gynäkologische Praxisklinik Harburg

Hamburg, City state of Hamburg, Germany

Albertinen-Krankenhaus, Brustzentrum

Hamburg, City state of Hamburg, Germany

Agaplesion Markus Krankenhaus

Frankfurt am Main, Hesse, Germany

Universitätsklinikum Brustzentrum

Frankfurt am Main, Hesse, Germany

Klinikum Frankfurt Höchst

Frankfurt am Main, Hesse, Germany

Main-Kinzig-Kliniken Gelnhausen

Gelnhausen, Hesse, Germany

Klinikum Hanau GmbH

Hanau, Hesse, Germany

Kreiskrankenhaus Bergstraße gGmbH

Heppenheim an der Bergstrasse, Hesse, Germany

Elisabeth Krankenhaus Kassel

Kassel, Hesse, Germany

Klinikum Kassel

Kassel, Hesse, Germany

Sana Klinikum Offenbach

Offenbach, Hesse, Germany

St. Josefs-Hospital, Frauenklinik

Wiesbaden, Hesse, Germany

Asklepios Paulinenklinik

Wiesbaden, Hesse, Germany

Helios Dr. Horst Schmidt Klinikum

Wiesbaden, Hesse, Germany

AKH Celle, Brustzentrum

Celle, Lower Saxony, Germany

Franziskus Hospital Harderberg

Georgsmarienhütte, Lower Saxony, Germany

Helios Klinikum Gifhorn

Gifhorn, Lower Saxony, Germany

Henriettenstiftung Frauenklinik

Hanover, Lower Saxony, Germany

Vinzenzkrankenhaus Hannover

Hanover, Lower Saxony, Germany

MHH Frauenklinik

Hanover, Lower Saxony, Germany

St. Bernward Krankenhaus

Hildesheim, Lower Saxony, Germany

Bonifatius-Hospital, Brustzentrum

Lingen, Lower Saxony, Germany

Euregio-Klinik Brustzentrum Nordhorn

Nordhorn, Lower Saxony, Germany

Agaplesion Ev. Klinikum, Brustzentrum Schaumburg

Obernkirchen, Lower Saxony, Germany

Klinikum Osnabrück

Osnabrück, Lower Saxony, Germany

Diakoniekrankenhaus, Frauenklinik

Rotenburg (Wümme), Lower Saxony, Germany

Klinikum Wolfsburg, Frauenklinik

Wolfsburg, Lower Saxony, Germany

Universität Greifswald, Frauenklinik

Greifswald, Mecklenburg-Vorpommern, Germany

Dietrich Bonhoeffer Klinikum, Brustzentrum

Neubrandenburg, Mecklenburg-Vorpommern, Germany

Universitäts-Frauenklinik

Rostock, Mecklenburg-Vorpommern, Germany

Helios Kliniken Schwerin

Schwerin, Mecklenburg-Vorpommern, Germany

Augusta-Klinik

Bochum, Nordrhein, Germany

Universitätsfrauenklinik Bonn

Bonn, Nordrhein, Germany

Marienhospital Bottrop

Bottrop, Nordrhein, Germany

Uniklinik Köln

Cologne, Nordrhein, Germany

St. Elisabeth Krankenhaus, Brustzentrum

Cologne, Nordrhein, Germany

Frauenklinik der H.-Heine-Universität

Düsseldorf, Nordrhein, Germany

Universitätsklinikum Essen Frauenklinik

Essen, Nordrhein, Germany

Kliniken Essen-Mitte

Essen, Nordrhein, Germany

Klinikum Märkische Kliniken, Brustzentrum

Lüdenscheid, Nordrhein, Germany

Klinikum Lünen, Brustzentrum

Lünen, Nordrhein, Germany

St. Franziskus-Hospital

Münster, Nordrhein, Germany

Universitätsklinikum Münster

Münster, Nordrhein, Germany

Marienkrankenhaus

Schwerte, Nordrhein, Germany

St. Marienkrankenhaus, Frauenklinik

Siegen, Nordrhein, Germany

St. Josef-Hospital, BZ Rhein-Sieg

Troisdorf, Nordrhein, Germany

Katharinen-Hospital, Brustzentrum

Unna, Nordrhein, Germany

Marien-Hospital

Wesel, Nordrhein, Germany

Westpfalz Klinikum

Kaiserslautern, Rhineland-Palatinate, Germany

BZ Mittelrhein Koblenz+Mayen

Koblenz, Rhineland-Palatinate, Germany

Klinikum Ludwigshafen

Ludwigshafen am Rhein, Rhineland-Palatinate, Germany

Diakonissen-Stiftungs-Krankenhaus Speyer

Speyer, Rhineland-Palatinate, Germany

Stadtkrankenhaus Worms

Worms, Rhineland-Palatinate, Germany

Krankenhaus St. Elisabeth und St. Barbara

Halle, Saint, Germany

Universität Halle/Saale, Frauenklinik

Halle, Saint, Germany

Klinik St. Marienstift

Magdeburg, Saint, Germany

Altmark-Klinikum Brustzentrum

Salzwedel, Saint, Germany

Johanniter-Krankenhaus, Frauenklinik

Stendal, Saint, Germany

Harzklinikum, Brustzentrum Harz

Wernigerode, Saint, Germany

Brustzentrum Nordsachsen

Borna, Saxony, Germany

Diakonissenkrankenhaus

Dresden, Saxony, Germany

Krankenhaus St. Joseph-Stift

Dresden, Saxony, Germany

Universität Dresden, Frauenklinik

Dresden, Saxony, Germany

Städtisches Klinikum

Görlitz, Saxony, Germany

Universitätsklinikum Leipzig, Brustzentrum

Leipzig, Saxony, Germany

St. Elisabeth Krankenhaus

Leipzig, Saxony, Germany

Klinikum Obergöltzsch Rodewisch

Rodewisch, Saxony, Germany

Helios Klinik

Schkeuditz, Saxony, Germany

Sana-Klinik

Eutin, Schleswig-Holstein, Germany

DIAKO Diakonissenkrankenhaus

Flensburg, Schleswig-Holstein, Germany

Universitätsklinikum Schleswig-Hostein

Kiel, Schleswig-Holstein, Germany

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Lübeck, Schleswig-Holstein, Germany

Charite Campus Mitte

Berlin, State of Berlin, Germany

Sana Klinikum Berlin-Lichtenberg

Berlin, State of Berlin, Germany

St. Gertrauden Krankenhaus

Berlin, State of Berlin, Germany

DRK Kliniken Köpenick

Berlin, State of Berlin, Germany

Park-Klinik Weißensee

Berlin, State of Berlin, Germany

Evang. Waldkrankenhaus Spandau

Berlin, State of Berlin, Germany

DRK-Kliniken Westend

Berlin, State of Berlin, Germany

Krankenhaus Waldfriede

Berlin, State of Berlin, Germany

Helios Klinikum, Klinik für Gynäkologie

Buch, State of Berlin, Germany

Hufeland-Klinik Bad Langensalza

Bad Langensalza, Thuringia, Germany

SRH Waldklinikum

Gera, Thuringia, Germany

Universitätsklinikum Jena

Jena, Thuringia, Germany

Helios Klinikum Meiningen, Brustzentrum

Meiningen, Thuringia, Germany

DRK Krankenhaus, Brustzentrum

Sömmerda, Thuringia, Germany

SRH Zentralklinikum Suhl

Suhl, Thuringia, Germany

Countries

Austria; Germany

References

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.

Reference Type: RESULT

PMID: 28331237 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32437921 (View on PubMed)

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.

Reference Type: RESULT

PMID: 36457648 (View on PubMed)

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.

Reference Type: RESULT

PMID: 37890350 (View on PubMed)

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.

Reference Type: RESULT

PMID: 39665649 (View on PubMed)

Other Identifiers

GBG 75 / ABCSG 43

Identifier Type: -

Identifier Source: org_study_id