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

Abstract

Background: In clinically node-negative breast cancer patients, the INSEMA trial (NCT02466737) assessed the non-inferiority of avoiding sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Here we present patient-reported outcomes (PROs) as a secondary endpoint.

Methods: PROs were assessed for patients with no axillary surgery, SLNB alone, and ALND. Quality of life (QoL) questionnaire EORTC QLQ-C30 and its breast cancer module (BR23) were used at baseline (pre-surgery) and 1, 3, 6, 12, and 18 months after surgery. The QoL scores were compared using repeated measures mixed models based on the safety set.

Findings: Between 2015 and 2019, 5502 patients were recruited for the first randomization, and 5154 were included in the intent-to-treat set (4124 SLNB versus 1030 no SLNB). In the case of one to three macrometastases after SLNB, 485 patients underwent second randomization (242 SLNB alone versus 243 ALND). Questionnaire completion response remained high throughout the trial: over 70% at all time points for the first randomization. There were significant differences for the BRBS (breast symptoms) and BRAS (arm symptoms) scores favoring the no SLNB group in all post-baseline assessments. Patients in the SLNB group showed significantly and clinically relevant higher scores for BRAS (differences in mean values ≥5.0 points at all times), including pain, arm swelling, and impaired mobility in all postoperative visits, with the highest difference at one month after surgery. Scoring of the QLQ-C30 questionnaire revealed no relevant differences between the treatment groups, although some comparisons were statistically significant.

Interpretation: This is one of the first randomized trials investigating the omission of SLNB in clinically node-negative patients and the first to report comprehensive QoL data. Patients with no SLNB benefitted regarding arm symptoms/functioning, while no relevant differences in other scales were seen.

Funding: Supported by German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany), Grant No. 110580 and Grant No. 70110580 to University Medicine Rostock.

Keywords: Axillary surgery; Breast cancer; Patient-reported outcomes; Quality of life; Sentinel lymph node biopsy.

Conflict of interest statement

Toralf Reimer: Complete funding of the INSEMA trial by two grants from the German Cancer Aid (Deutsche Krebshilfe). All payments to the University Medicine Rostock (UMR), Germany. Grant from the Else Kroener-Fresenius Foundation for EUBREAST-01 trial; payment to the UMR. Grant from the German Society of Senology for EUBREAST-01 trial; payment to the UMR. Payment for presentations from Roche, Pfizer, AstraZeneca, Novartis, and Daiichi-Sankyo. Angrit Stachs: no declared conflicts of interest. Kristina Veselinovic: Payment or honoraria for presentations from Roche, Novartis, AstraZeneca, and Lilly. Silke Polata: no declared conflicts of interest. Thomas Müller: no declared conflicts of interest. Thorsten Kühn: no declared conflicts of interest. Jörg Heil: no declared conflicts of interest. Beyhan Ataseven: no declared conflicts of interest. Roland Reitsamer: no declared conflicts of interest. Guido Hildebrandt: no declared conflicts of interest. Michael Knauer: Participation of Data Safety Monitoring Board for WSG (Westdeutsche Studiengruppe, Germany). Leadership Swiss Society of Senology. Michael Golatta: Grants/contracts from Siemens Healthcare GmbH and Samantree medical. Honoraria from Samantree medical for presentation (ESSO40). Advisory Board Medbotics (twice a year). Andrea Stefek: no declared conflicts of interest. Dirk-Michael Zahm: no declared conflicts of interest. Marc Thill: Grants/contracts from Exact Sciences and Endomag, payment to my institution. Consulting fees from Agendia, Amgen, AstraZeneca, Becton and Dickinson, Clearcut, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Grünenthal, GSK, Lilly, Norgine, Neodynamics, Novartis, Onkowissen, Organon, Pfizer, Pfm medical, Pierre Fabre, Roche, RTI Surgical, Seagen, Sirius Pintuition, and Sysmex. Honoraria for presentations from Amgen, AstraZeneca, Connect Medica, Eisai, Exact Sciences, Gedeon Richter, Gilead Sciences, GSK, Hexal, I-Med-Institute, Joerg Eickeler, Lilly, MCI, Medscape, MSD, Medtronic, Novartis, Onkowissen, Pfizer, Pfm medical, Roche, Seagen, Streamed UP, Sysmex, Vifor, Viatris, and Servier. Support for attending meetings from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Hexal, Neodynamics, Clearcut, Novartis, Pfizer, Roche, Eisai, Exact Sciences, Art Tempi, Pfm medical, Roche, Hexal, MCI, Lilly, MSD, Norgine, Novartis, Pfizer, RTI Surgical, and Seagen. Leadership AWOgyn (chair of the board of directors) and DGGG (member of the board of directors). Receipt of equipment, materials, drugs, medical writing, gifts or other services from Roche, Servier, AstraZeneca, Celgene, RTI Surgical, Novartis, Amgen, Roche, Clearcut, and Pfm medical. Valentina Nekljudova: Grants/contracts from Abbvie, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Novartis, Pfizer and Roche. Royalties or licenses from VM Scope GmbH. Patents planned, issued or pending: EP14153692.0, EP21152186.9, EP15702464.7, and EP19808852.8. David Krug: no declared conflicts of interest. Sibylle Loibl: Grants/contracts from Abbvie, AstraZeneca, DSI, Celgene, Gilead, Novartis, Pfizer, Roche, and Molecular H. Royalties or licenses: Digital Ki67 Evaluator. Honoraria for lectures from AstraZeneca, DSI, Gilead, Novartis, Pfizer, and Roche. Honoraria for medical writing from DSI, Gilead, Novartis, Pfizer, Roche, and Seagen. Patents planned, issued or pending: EP14153692.0, EP21152186.9, EP15702464.7, and EP19808852.8. Participation on a Data Safety Monitoring Board or Advisory Board: Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, Eisai Europe, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen. Bernd Gerber: no declared conflicts of interest.

© 2022 The Authors.

Figures

Fig. 1

CONSORT diagram. Abbreviations: SLNB = sentinel lymph node biopsy; ITT = intention-to-treat; perf. = performed; SLN = sentinel lymph node; ALND = axillary lymph node dissection; neg. = negative; pos. = positive; LN = lymph node.

Fig. 2

Curves for PROs concerning QLQ-BR23 arm symptoms (BRAS scales) and first randomization. A: overall with P-values for Treatment, Time, and Treatment by time; B: pain in arm or shoulder; C: swelling in arm or hand; and D: arm mobility limited.

Fig. 3

Curves for PROs concerning QLQ-BR23 arm symptoms (BRAS scale) and second randomization. A: overall with P-values for Treatment, Time, and Treatment by time; B: pain in arm or shoulder; C: swelling in arm or hand; and D: arm mobility limited.

Fig. 4

Curves for PROs concerning QLQ-BR23 breast symptoms (BRBS scales) and first randomization. A: overall with P-values for Treatment, Time, and Treatment by time; B: pain in the breast; C: swelling in the breast; D: hypersensitivity breast; and E: other skin problems in the breast.

Fig. 5

Curves for PROs concerning QLQ-BR23 breast symptoms (BRBS scales) and second randomization. A: overall with P-values for Treatment, Time, and Treatment by time; B: pain in the breast; C: swelling in the breast; D: hypersensitivity breast; and E: other skin problems in the breast.