Original ResearchUnilateral or bilateral irradiation in cervical lymph node metastases of unknown primary? A retrospective cohort study☆
Introduction
Head and neck cancer of unknown primary (CUP) represents 1%–4% of head and neck tumours [1], [2]. Their diagnostic workup includes fine-needle aspiration (FNA) of the node(s), positron-emission tomography–computed tomography (PET-CT) and panendoscopy usually with tonsillectomy and/or mucosectomy [3], [4], [5], [6], [7], [8], [9], [10], [11], as well as human papilloma virus (HPV) and Epstein–Barr virus (EBV) testing since the 2017 tumour-node-metastasis (TNM) classification [12]. Neck dissection is used both as a diagnostic and therapeutic modality. Irradiation aims to prevent regional relapse (≈10% of patients) [8], [13], [14] and metachronous mucosal failure of the upper aerodigestive tract (≈5–15%) [5], [9], [15]. A current area of controversy is whether selective or extensive irradiation of nodal areas should be performed and whether de-escalation of mucosal irradiation can be performed based on the low relapse rates, toxicity of extensive irradiation and presumed rates of HPV-related carcinomas. On the other hand, intensity-modulated radiation therapy (IMRT) has improved the tolerance to extensive nodal and mucosal irradiation to the point where it may prevent more locoregional relapses than elective irradiation while minimising toxicity [2], [16], [17]. Owing to the rarity of CUP, however, the level of evidence is currently based only on retrospective studies of less than 200 patients [1], [18], [19], [20], [21], [22], [23], [24]. To date, no prospective randomised trial has ever been completed to advocate for or against either strategy, as the sole randomised trial (NCT00047125; unpublished) started was terminated early because of insufficient accrual.
We aimed to assess whether bilateral and unilateral nodal neck irradiation resulted in different outcomes in terms of local and regional control and of toxicities.
Section snippets
Materials and methods
This institutional review board– and ethical committee–approved retrospective, multicentre and international study included patients irradiated for CUP between 2000 and 2015. Patients with squamous cell CUP were included after proper diagnostic workup showing absence of distant metastases and a histology-proven diagnosis of carcinoma and were treated with curative external beam radiotherapy (RT). The diagnostic work up has changed over time. For example, the use of PET-CT has become more
Results
From 2000 to 2015, 377 patients were irradiated for CUP, of whom 27 were excluded due to other histology (n = 2), no RT (n = 1) or insufficient follow-up data (n = 20). Patient and tumour characteristics of the 350 patients treated in 20 institutions are presented in Table 1. Patients with N2a/b disease represented the majority of the population, but N3 disease was also frequently observed. A majority (74.5%) of patients had unilateral nodal disease, whereas 82 (25.5%) patients had N2c or
Discussion
With 350 patients, the present study is the largest to date in a rare subgroup of head and neck cancers, and it specifically addressed ‘standard’ bilateral extended nodal volume irradiation versus de-escalation with unilateral (often elective) nodal irradiation in patients with CUP. Most patients underwent bilateral irradiation; 52.2% of them had bilateral irradiation for unilateral nodal disease, whereas 20.5% of them had unilateral irradiation for unilateral disease. Of note, IMRT became a
Conclusion
This large study of cervical lymphadenopathies of unknown primary suggests that unilateral neck irradiation may not yet be the treatment standard, as it may result in slightly worse rates of mucosal and nodal relapse. Severe toxicities were, however, more frequent after bilateral irradiation than unilateral irradiation. Molecular biomarkers are probably necessary to better predict the primary site of origin in a way that is adapted for the neck levels involved. However, not all CUPs are
Acknowledgements
The manuscript has been revised for the English by an independent scientific language editing service (Angloscribe).
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Financing: CHU de Besançon – CH de Belfort-Montbéliard - Institut de Cancérologie de Lorraine.
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equally contributed to the manuscript.