Abstract
PurposeNone of the key randomised trials on the omission of axillary lymph node dissection (ALND) in sentinel lymph-positive breast cancer have reported external validity, even though results indicate selection bias. Our aim was to assess the external validity of the ongoing randomised SENOMAC trial by comparing characteristics of Swedish SENOMAC trial participants with non-included eligible patients registered in the Swedish National Breast Cancer Register (NKBC).MethodsIn the ongoing non-inferiority European SENOMAC trial, clinically node-negative cT1–T3 breast cancer patients with up to two sentinel lymph node macrometastases are randomised to undergo completion ALND or not. Both breast-conserving surgery and mastectomy are eligible interventions. Data from NKBC were extracted for the years 2016 and 2017, and patient and tumour characteristics compared with Swedish trial participants from the same years.ResultsOverall, 306 NKBC cases from non-participating and 847 NKBC cases from participating sites (excluding SENOMAC participants) were compared with 463 SENOMAC trial participants. Patients belonging to the middle age groups (p = 0.015), with smaller tumours (p = 0.013) treated by breast-conserving therapy (50.3 versus 47.1 versus 65.2%, p < 0.001) and less nodal tumour burden (only 1 macrometastasis in 78.8 versus 79.9 versus 87.3%, p = 0.001) were over-represented in the trial population. Time trends indicated, however, that differences may be mitigated over time.ConclusionsThis interim external validity analysis specifically addresses selection mechanisms during an ongoing trial, potentially increasing generalisability by the time full accrual is reached. Similar validity checks should be an integral part of prospective clinical trials.Trial registration: NCT 02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015
Highlights
Several large randomised clinical trials (RCTs) de-escalating axillary treatment interventions in sentinel lymph node (SLN)-positive breast cancer have revolutionised the clinical management of limited axillary nodal metastases [1,2,3,4], and results from further clinical trials, both ongoing (INSEMA [5], SENOMAC [6], POSNOC [7]) and completed (SOUND [8]), are eagerly awaited
The ACOSOG Z0011 and IBCSG 23-01 trials substantially changed routine management of breast cancer patients with 1–2 sentinel lymph node metastases. The former trial, Z0011, included patients with tumours up to 5 cm in size and up to two nodal metastases treated by breast-conserving surgery combined with whole-breast radiotherapy
A similar observation is true for the IBCSG 23-01 trial, where only patients with micrometastatic SLNs were eligible: While the size of micrometastases can be ≤ 2 mm, the observed size of micrometastases was ≤ 1 mm in 69% and 70% of cases in the respective groups [1]
Summary
Several large randomised clinical trials (RCTs) de-escalating axillary treatment interventions in sentinel lymph node (SLN)-positive breast cancer have revolutionised the clinical management of limited axillary nodal metastases [1,2,3,4], and results from further clinical trials, both ongoing (INSEMA [5], SENOMAC [6], POSNOC [7]) and completed (SOUND [8]), are eagerly awaited. Trial participants should be comparable to clinical practice patients in both patient and tumour characteristics, and the standard treatment within and outside a Breast Cancer Research and Treatment (2020) 180:167–176 trial should be the same It is the clinical practice population to whom clinical trial results will be applied, and divergences in characteristics will negatively affect external validity of a trial, in the worst case jeopardising a successful and safe implementation of the trial’s results. The ACOSOG Z0011 and IBCSG 23-01 trials substantially changed routine management of breast cancer patients with 1–2 sentinel lymph node metastases. The former trial, Z0011, included patients with tumours up to 5 cm in size and up to two nodal metastases (which could be either macro- or micrometastases) treated by breast-conserving surgery combined with whole-breast radiotherapy. A similar observation is true for the IBCSG 23-01 trial, where only patients with micrometastatic SLNs were eligible: While the size of micrometastases can be ≤ 2 mm, the observed size of micrometastases was ≤ 1 mm in 69% and 70% of cases in the respective groups [1]
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