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Up-front neck dissection followed by definitive (chemo)-radiotherapy in head and neck squamous cell carcinoma: Rationale, complications, toxicity rates, and oncological outcomes – A systematic review

      Abstract

      Background and purpose: Lymph node metastases of head and neck cancer are considered one of the most negative prognostic factors. While outcomes and feasibility of chemo-radiotherapy ((C)RT) with or without adjuvant planned neck dissection (ND) in organ-preservation treatment strategy have been addressed, the role of ND before (C)RT, called up-front neck dissection (UFND), is not clearly established. This review provides a critical appraisal of UFND. Material and methods: Articles were identified with a systematic approach. Outcomes included post-UFND delay of (C)RT, surgical complications, radiation toxicity and oncologic outcome. Results: Fifteen studies met inclusion criteria, totaling 607 patients undergoing UFND. Part of the data suggest advantages toward less surgical complications compared with salvage ND, decreased serious acute radiation toxicity and better oncological outcomes when compared with (C)RT alone. The overall heterogeneity of the analyzed data does not allow a meta-analysis that provides high-quality evidence in favor or against UFND. Conclusions: Due to lack of well-designed randomized trials, it is difficult to assess the role of UFND in organ-preserving (C)RT setting of head and neck cancer.

      Keywords

      Lymph node metastases of head and neck squamous cell carcinoma (HNSCC) are frequent and considered one of the most important prognostic factors, resulting in decreased survival by at least 50% [
      • Cachin Y.
      • Sancho-Garnier H.
      • Micheau C.
      • Marandas P.
      Nodal metastasis from carcinomas of the oropharynx.
      ]. The successful management of the neck is one of the main pillars in the treatment of HNSCC.
      Surgery to the primary tumor with modified radical or radical neck dissection (ND) followed by adjuvant postoperative radiation therapy (RT) with or without concomitant chemotherapy ((C)RT) has been the conventional management of cN2 and cN3 in HNSCC. Therefore, progresses achieved over the last decades have also established radiotherapy (RT) as a means of effective disease control with similar survival rates than the above mentioned surgical strategy. Some advances include altered fractionation RT, intensity-modulated radiotherapy (IMRT), and combination of chemotherapy or non-cytotoxic molecular targeted agents with radiation [
      • Bourhis J.
      • Overgaard J.
      • Audry H.
      • et al.
      Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.
      ,
      • Pignon J.-P.
      • le Maître A.
      • Maillard E.
      • Bourhis J.
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
      ,
      • Nutting C.M.
      • Morden J.P.
      • Harrington K.J.
      • et al.
      Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.
      ,
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ]. Single modality approaches with surgery or RT alone is recommended for patients with early-stage tumors (UICC stages I–II), whereas combined modalities, like surgery followed by RT with or without concomitant chemotherapy are generally performed for loco-regionally advanced disease (UICC stages III–IV) [
      • Thariat J.
      • Hamoir M.
      • Garrel R.
      • et al.
      Management of the neck in the setting of definitive chemoradiation: is there a consensus? A GETTEC study.
      ,

      “National Comprehensive Cancer Network”. National Comprehensive Cancer Network Guidelines for Head and Neck Cancers (version 2.2013). 2013.

      ,
      • Barkley H.T.
      • Fletcher G.H.
      • Jesse R.H.
      • Lindberg R.D.
      Management of cervical lymph node metastases in squamous cell carcinoma of the tonsillar fossa, base of tongue, supraglottic larynx, and hypopharynx.
      ]. In the past two decades, radical CRT has also become a widely accepted treatment alternative to primary surgery, with the advantage of organ-preservation in selected locally advanced HNSCC cases [
      • Pignon J.-P.
      • le Maître A.
      • Maillard E.
      • Bourhis J.
      Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients.
      ].
      There seems to be a relative consensus for the management of the neck in cN0–1 patients. In case of surgical management of the primary tumor, elective neck dissection (ND) is performed during the same surgery. In small oral cavity and selected oropharynx cancers, the debate whether to perform elective ND or sentinel lymph node biopsy is ongoing [
      • Govers T.M.
      • Hannink G.
      • Merkx M.A.
      • Takes R.P.
      • Rovers M.M.
      Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis.
      ,
      • Civantos F.J.
      • Zitsch R.P.
      • Schuller D.E.
      • et al.
      Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1–T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial.
      ,
      • Alkureishi L.W.T.
      • Ross G.L.
      • Shoaib T.
      • et al.
      Sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-up of a European multicenter trial.
      ,
      • Pezier T.
      • Nixon I.J.
      • Gurney B.
      • et al.
      Sentinel lymph node biopsy for T1/T2 oral cavity squamous cell carcinoma–a prospective case series.
      ,
      • Broglie M.A.
      • Haerle S.K.
      • Huber G.F.
      • Haile S.R.
      • Stoeckli S.J.
      Occult metastases detected by sentinel node biopsy in patients with early oral and oropharyngeal squamous cell carcinomas: impact on survival.
      ,
      • Samant S.
      Sentinel node biopsy as an alternative to elective neck dissection for staging of early oral carcinoma.
      ]. In case of primary RT, elective ND can be considered unnecessary due to excellent nodal control rates. However, with the shift toward organ-preserving strategies, the role of ND is not clearly established for cN2–3 disease. As large and/or hypoxic lymph node metastases are generally less responsive than the primary tumor, planned ND independent of the treatment response or salvage ND only for residual or recurrent nodal disease after (C)RT for advanced HNSCC have been included into these treatment protocols. Stenson et al. reported 35% of ND specimens with microscopic residual tumor in the lymph nodes after CRT [
      • Stenson K.M.
      • Haraf D.J.
      • Pelzer H.
      • et al.
      The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection.
      ]. The efficacy of post-RT ND depending on the treatment response, after either RT alone or CRT has been reported in a number of series [
      • Sanguineti G.
      • Califano J.
      • Stafford E.
      • et al.
      Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma.
      ,
      • Chan A.W.
      • Ancukiewicz M.
      • Carballo N.
      • Montgomery W.
      • Wang C.C.
      The role of postradiotherapy neck dissection in supraglottic carcinoma.
      ,
      • Vongtama R.
      • Lee M.
      • Kim B.
      • et al.
      Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.
      ,
      • Yao M.
      • Hoffman H.T.
      • Chang K.
      • et al.
      Is planned neck dissection necessary for head and neck cancer after intensity-modulated radiotherapy?.
      ,
      • Karakaya E.
      • Yetmen O.
      • Oksuz D.C.
      • et al.
      Outcomes following chemoradiotherapy for N3 head and neck squamous cell carcinoma without a planned neck dissection.
      ,
      • Karakaya E.
      • Yetmen O.
      • Oksuz D.C.
      • et al.
      Chemoradiotherapy for N2 head and neck squamous cell carcinoma – outcomes without a planned neck dissection: our experience in two hundred and seven patients.
      ,
      • Narayan K.
      • Crane C.
      • Kleid S.
      • Hughes P.
      • Peters L.
      Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?.
      ,
      • Ahmed K.A.
      • Robbins K.T.
      • Wong F.
      • Salazar J.E.
      Efficacy of concomitant chemoradiation and surgical salvage for N3 nodal disease associated with upper aerodigestive tract carcinoma.
      ,
      • Ganly I.
      • Bocker J.
      • Carlson D.L.
      • et al.
      Viable tumor in postchemoradiation neck dissection specimens as an indicator of poor outcome.
      ,
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ,
      • Brizel D.M.
      • Albers M.E.
      • Fisher S.R.
      • et al.
      Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.
      ]. Nevertheless, nodal control rates with and without post-(C)RT planned ND ranged between 55–100% [
      • Narayan K.
      • Crane C.
      • Kleid S.
      • Hughes P.
      • Peters L.
      Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?.
      ,
      • Ahmed K.A.
      • Robbins K.T.
      • Wong F.
      • Salazar J.E.
      Efficacy of concomitant chemoradiation and surgical salvage for N3 nodal disease associated with upper aerodigestive tract carcinoma.
      ,
      • Ganly I.
      • Bocker J.
      • Carlson D.L.
      • et al.
      Viable tumor in postchemoradiation neck dissection specimens as an indicator of poor outcome.
      ,
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ,
      • Brizel D.M.
      • Albers M.E.
      • Fisher S.R.
      • et al.
      Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.
      ] and 56–100% [
      • Sanguineti G.
      • Califano J.
      • Stafford E.
      • et al.
      Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma.
      ,
      • Chan A.W.
      • Ancukiewicz M.
      • Carballo N.
      • Montgomery W.
      • Wang C.C.
      The role of postradiotherapy neck dissection in supraglottic carcinoma.
      ,
      • Vongtama R.
      • Lee M.
      • Kim B.
      • et al.
      Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.
      ,
      • Yao M.
      • Hoffman H.T.
      • Chang K.
      • et al.
      Is planned neck dissection necessary for head and neck cancer after intensity-modulated radiotherapy?.
      ,
      • Karakaya E.
      • Yetmen O.
      • Oksuz D.C.
      • et al.
      Outcomes following chemoradiotherapy for N3 head and neck squamous cell carcinoma without a planned neck dissection.
      ,
      • Karakaya E.
      • Yetmen O.
      • Oksuz D.C.
      • et al.
      Chemoradiotherapy for N2 head and neck squamous cell carcinoma – outcomes without a planned neck dissection: our experience in two hundred and seven patients.
      ,
      • Corry J.
      • Peters L.
      • Fisher R.
      • et al.
      N2–N3 neck nodal control without planned neck dissection for clinical/radiologic complete responders-results of Trans Tasman Radiation Oncology Group Study 98.02.
      ], respectively. Additionally, it has been shown in several studies that a ND after (C)RT increases the risk of delayed wound healing and other postoperative complications. Local and systemic complication rates after ND of the previously irradiated region varied from 5% to 77% [
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Davidson B.J.
      • Newkirk K.A.
      • Harter K.W.
      • Picken C.A.
      • Cullen K.J.
      • Sessions R.B.
      Complications from planned, posttreatment neck dissections.
      ,
      • Frank D.K.
      • Hu K.S.
      • Culliney B.E.
      • et al.
      Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer.
      ,
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Mabanta S.R.
      • Mendenhall W.M.
      • Stringer S.P.
      • Cassisi N.J.
      Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes.
      ], with severe late grade 3 toxicity reported as high as 55% [
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Machtay M.
      • Moughan J.
      • Trotti A.
      • et al.
      Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis.
      ].
      In attempt to decrease the risk of postoperative complications and to increase a better regional control, planned ND without surgery to the primary tumor before (C)RT in patients with advanced HNSCC has been employed in organ-preservation strategy. The so called up-front ND (UFND) is currently less known and performed [
      • Thariat J.
      • Hamoir M.
      • Garrel R.
      • et al.
      Management of the neck in the setting of definitive chemoradiation: is there a consensus? A GETTEC study.
      ], but confers the advantages of avoiding adjuvant surgery on a previously irradiated neck as well as the removal of hypoxic tissues and bulky nodal metastases, which may be less responsive to (C)RT and possibly associated to an increased risk of distant metastases [
      • Aebersold D.M.
      • Kollar A.
      • Beer K.T.
      • Laissue J.
      • Greiner R.H.
      • Djonov V.
      Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation.
      ,
      • Aebersold D.M.
      • Landt O.
      • Berthou S.
      • et al.
      Prevalence and clinical impact of Met Y1253D-activating point mutation in radiotherapy-treated squamous cell cancer of the oropharynx.
      ,
      • De Bacco F.
      • Luraghi P.
      • Medico E.
      • et al.
      Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer.
      ]. Satisfying control and postoperative complication rates with UFND, along with minimal delay of definitive treatment, have been reported previously [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ]. Despite the good results of UFND, many authors consider this approach as a redundant strategy, since definitive (C)RT will take place to the primary tumor site and the neck [
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ,
      • Hamoir M.
      • Ferlito A.
      • Schmitz S.
      • et al.
      The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease.
      ]. Still, questions about sequencing and/or exact requirements for ND in organ-preserving concomitant CRT strategies remain unanswered.
      We hereby performed a systematic review on UFND in HNSCC. This work has the purpose to present treatment-related complications, toxicity rates and oncological outcomes as well to discuss the current role of UFND.

      Materials and methods

      Identification of studies and data extraction

      Two independent authors (OE and LN) conducted a systematic literature search in MEDLINE and SCOPUS databases without any constraint for the starting date until December 2013. In addition, meeting abstracts were searched in congress books of the American Head and Neck Society, the American Society for Radiation Oncology, the European Society for Radiation Oncology, the European Cancer Congress and the American Society of Clinical Oncology between 2011 and 2013. The search terms used implementing Boolean algorithms were: “Head and Neck Neoplasms[Mesh], split, therapy, up-front, upfront, planned, before, followed by, neck, dissect∗ and thyroid∗ (for exclusion). For Scopus and abstract books the following query terms were used: neck, dissect∗, split, therapy, upfront, up-front, planned, before, followed by, and thyroid∗ (for exclusion) within the category of medicine. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed to document details on the search strategy and selection processes [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ].

      Inclusion criteria

      We included publications concerning patients with HNSCC of oral cavity, oropharynx, hypopharynx and larynx. Studies had to contain patients treated with UFND before definitive RT with or without concomitant chemotherapy to the unresected primary tumor and lymphatic levels according to clinical and pathological findings. At least one of the following endpoints had to be reported for the UFND patients: regional control, loco-regional control (LRC), disease-free survival (DFS), overall survival (OS), post-operative complications or RT toxicity. Due to the sparsity of data we did not limit our search to studies necessarily having a comparator group or a specific design. Treatment strategies with exclusively neoadjuvant/induction chemotherapy before surgery were excluded.
      Extracted data were recorded into standardized spread sheets according to the following parameters: author, year of publication, study period, study design, follow-up time, mean age of patients, number of treatment arms/groups, total number of patients, number of patients treated with UFND, types of UFND, RT technique and dose, chemotherapy regimen used (if any), disease and patient characteristics, delay of definitive treatment after UFND, explanation of the additional arm(s) (if any), patterns of failure (primary tumor and/or neck), LRC rate, OS, DFS, distant metastasis-free survival (DMFS), disease-specific survival (DSS), RT dose reduction secondary to UFND, post-operative complications, and RT toxicity.

      Results

      Search results

      The literature search yielded a total of 1131 articles and abstracts. Only 15 of those met all inclusion criteria and were considered for final analysis [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ]. A flowchart detailing the number of screened, included and excluded articles, as well as the reasons for exclusion is provided in Fig. 1. All included studies were published in the last 25 years. No articles were excluded because of language.
      Figure thumbnail gr1
      Fig. 1PRISMA flowchart with identified, screened and included articles. PRISMA: preferred reporting items for systematic reviews and meta-analyses, UFND: up-front neck dissection.

      Patients’ characteristics and study designs (Table 1, Table 2)

      The total number of patients reported with UFND was 607. Patients in the reported study cohorts were treated between 1972 and 2010. Of the 15 studies, 13 were retrospective [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ] and 2 were prospective [
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ]. Patients were allocated to a single arm in 9 studies (UFND only) whereas 6 articles described more than one arm (Table 1, Table 2). The cohort sizes of patients with UFND ranged from 15 to 94 patients. In the studies with more than one arm, the percentage of patients in the UFND cohort ranged from 17% to 86%. Treatment modalities for groups other than UFND had extreme variations through studies. Groups/arms other than UFND and (C)RT contained surgery to the primary tumor and ND with the addition of post-operative RT in one study [
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ] and (C)RT alone without planned ND in the remaining studies (Table 2) [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ]. Salvage NDs were performed in case of less than complete clinical response or recurrence. One study [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ] included a third group with 8 additional patients treated with single nodal excision prior to RT.
      Table 1Patients’ characteristics and study design.
      Author & yearStudy typeStudy periodFollow-up (years)Age (range)Arms/groupsN. of UFND patients (total)UFND typeRT techniqueDose to neck (Gy)cCX
      Brugere
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      1991
      R1984–1987⩾5 (m.)m.: 58 (35–85)365 (313)61 RND, 4 MRNDnornorNo
      Byers
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      1992
      R1972–1988⩾2 (m.)md.: 61 (43–78)135 (35)“functional ND”nor⩾50No
      Verschuur
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      1996
      R1985–19923.9 (m.)m.: 52.9 (32–78)115 (15)13 RND, 2 MRNDnor66–80No
      Peters
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      1996
      R1984–19933.3 (md.)md.: 59 (34–83)317 (100)17 MRND2D54No
      Allal
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      1999
      R1991–19962.6 (md.)m.: 57 (nor)224 (41)23 RND, 1 MRND2D⩾50.46 cases
      Smeele
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      2000
      R1988–19982.6 (m.)m.: 64 (40–87)132 (37)
      Remaining patients either not irradiated, did not complete treatment or irradiated for palliative intention.
      25 RND, 7 MRNDnor⩾60No
      Carinci
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      2001
      P rando-mized1991–1997⩾2 (m.)md.: 62 (44–77)223 (54)2 RND, 21 “functional ND”nornorCisplatin + 5FU
      Reddy
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      2005
      R1996–20033.2 (m.)md.: 55116 (16)1 RND, 13 MRND, 2 SND2D50–60“if necessary”
      D’Cruz
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      2006
      P single arm1993–20032.1 (md.)md.: 56 (39–73)152 (52)RND and MRND2D46–60No
      Cupino
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      2007
      R2000–20033 (md.)md.: 55 (41–75)125 (25)SND3DCRT + IMRT50–66Weekly paclitaxel and/or platinum
      Prades
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      2008
      R1996–2002⩾1.5 (m.)m.: 54 (35–70)176 (76)19 RND, 42 MRND, 11 SND, 4 bilateral NDnor50–75Mixed in time
      Paximadis
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      2012
      R2000–20093.9 (md.)m.: 53 (40–74)155 (55)11 RND, 44 MRND3DCRT + IMRT50–66Platinum or cetuximab
      Liu
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      2012
      R1999–20054.1 (md.)m.: 56 (39–76)246 (85)29 MRND, 12 RND, 5 bilateral ND2D50–7224 cases with cisplatin after 2003 (induction (n = 20) before 2003)
      Al-Mamgani
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      2013
      R1996–20102.8 (md.)md.: 60 (38–87)232 (135)4 RND, 15 MRND, 13 SND3DCRT + IMRT46–669 cases with cisplatin
      Shenoy
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      2013
      R1991–20082 (md.)md.: 54 (32–70)194 (109)
      Remaining patients either not irradiated, did not complete treatment or irradiated for palliative intention.
      55 RND, 39 MRND”RT with or without [planning] CT”60–6624 cases (mostly N3) weekly cisplatin
      cCX: concomitant chemotherapy, CT: Computed Tomography, IMRT: Intensity modulated radiotherapy, m.: mean, md.: median, MRND: modified radical neck dissection, ND: neck dissection, nor: not reported, P: prospective, R: retrospective, RND: radical neck dissection, RT: radiotherapy, SND: selective neck dissection, UFND: up-front neck dissection, 2DRT: two-dimensional conventional radiotherapy, 3DCRT: three-dimensional conformal radiotherapy, 5FU: 5-Fluorouracil.
      low asterisk Remaining patients either not irradiated, did not complete treatment or irradiated for palliative intention.
      Table 2Description of studies with more than one arm.
      Author & yearDescription of additional arms other than UFNDDifferences regarding characteristics or treatment
      Brugere
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      1991
      2nd (n = 53): partial laryngectomy + ND + adjuvant RT

      3rd (n = 195): RT without planned ND
      nod
      Peters
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      1996
      2nd (n = 75): induction chemotherapy (n = 6) + RT without planned ND

      3rd (n = 8): up-front single node excision
      nor
      Allal
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      1999
      2nd (n = 17): RT ± concomitant chemotherapy (n = 8) without planned NDSimilar median doses to involved nodes (69.9 Gy), with ranges of 56.4–70.4 Gy and 67.5 to 69.9 Gy in groups with and without UFND, respectively
      Carinci
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      2001
      2nd (n = 31): CRT with cisplatin + 5FU without planned NDCRT alone arm contained 6 patients with cN3 disease whereas UFND + CRT had none
      Liu
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      2012
      2nd (n = 39): induction chemotherapy (n = 19) + CRT with different schedules without planned NDnod
      Al-Mamgani
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      2013
      2nd (n = 103): RT ± concomitant cisplatin (77%) without planned NDMore patients in group 2 had advanced disease (T3–4) compared to group 1 (p = 0.007)

      More patients in group 2 were treated with concomitant cisplatin (77% vs 28%, p < 0.0001)
      CR: complete response, CRT: concomitant chemoradiotherapy, ND: neck dissection, nod: no difference, nor: not reported, RT: radiotherapy, UFND: up-front neck dissection, 5FU: 5-Fluorouracil.
      The types of UFND were modified radical and radical ND in the majority of cases. RT technique was not described in 7 studies [
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ]. Two-dimensional conventional RT was reported in 5 studies [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ]. Three-dimensional conformal and IMRT techniques were described in 3 studies [
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ]. Most of the study cohorts were treated in an era when the use of concomitant chemotherapy was not established as standard (published until 2001). Before this date, only Allal et al. (1999) treated some patients with concomitant CRT [
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ]. Except for one study [
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ], concomitant CRT was preferred in all studies published after 2001. Descriptive data of follow-up time varied across publications (e.g. mean, median, “at least”), but all studies had at least 1.5 year follow-up (Table 1).

      Disease characteristics (Supplementary Table 1)

      The distribution of disease characteristics varied markedly among the studies. Some authors only reported the general characteristics of the whole cohort without the details of patients treated with UFND. Most common primary site was hypopharynx (45%), followed by oropharynx (38%), larynx (16%) and oral cavity (<1%). All studies included patients having nodal positive necks (cN1–3) except 3 articles [
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ] containing 1–5 cN0 cases (2–22%). The majority of the cases had cN2–3, stage IVA/B disease. However, it should be noted that different versions of the AJCC/UICC for TNM staging were used depending on the publication date. HNSCC was the only histology with the exception of 3 undifferentiated carcinomas of tonsil (2 patients) and piriform sinus (1 patient) included in one study [
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ].

      Delay of (chemo)-radiotherapy due to UFND and postoperative complications (Supplementary Table 2)

      Time interval between UFND and (C)RT was reported in 10 articles [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ], some reporting median, some mean values. It can be interpreted that (C)RT began around the 4th week after the UFND (range: 10–75 days). Two authors assessed the impact of RT delay on oncological outcome. Byers et al. [
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ] found that a delay greater than 14 days to start RT following UFND was significantly associated with inferior overall survival (p = 0.01, only Kaplan–Meier curves provided), whereas Smeele et al. [
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ] could not show any significant impact on outcome.
      When details were provided in the article, surgery-related complications due to UFND were categorized as minor (wound complications not requiring an intervention or causing any permanent damage to structures) or major (local problems requiring surgical intervention, systemic complications requiring intensive care or causing permanent loss of function). Post-UFND complications were reported in 13 studies. Eight of them reported total post-operative complication rates of less than 10% [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ] whereas the remaining 5 studies showed complications between 12% and 37% [
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ]. Post-operative complications were assessed in 2 studies comparing strategies with and without UFND [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ]. Surgical complications were reported to be lower after UFND (8%) compared to salvage ND for nodal persistence/recurrence (12.5%) by Peters et al. [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ]. According to Liu et al. [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ] complication rates after UFND were 7% vs. 77% (54% major complications, half of them requiring pectoral major myocutaneous flap and the other half requiring additional surgery) after salvage ND for nodal persistence/recurrence. Unfortunately, no statistical analyses were performed in these articles and it is not clearly reported whether the salvage surgery was only performed for isolated neck failure or included also patients with surgery for synchronous loco-regional relapses, which would explain the reason for much higher complication rates.

      Toxicity after (chemo)-radiotherapy (Supplementary Table 3)

      (C)RT toxicities were poorly reported. Skin and soft tissue toxicities in the neck region were rarely described separately. Six authors [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ] did not mention toxicity and in the other 9 articles [
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ] different scales or subjective evaluations were used. Percentage of “serious” or grade ⩾ 3 toxicities ranged from 0% to 80% for acute [
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ] and 0–20% for late toxicities [
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ] among cases treated with UFND strategy. Two authors compared grade ⩾ 3 toxicities among the groups treated with and without UFND: Allal et al. [
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ] found no significant differences for acute (80% vs. 86%) and late toxicities (8% vs. 6%), whereas Al-Mamgani [
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ] reported significantly higher grade 3 acute toxicity in patients treated with (C)RT alone (72% vs. 50%, p = 0.02). However in the latter, (C)RT alone group consisted of patients with more advanced stage disease requiring larger RT fields compared to patients who underwent UFND prior to (C)RT. Additionally, Peters et al. [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ] reported fibrosis rates of 20% and 24% with and without UFND, but no statistical comparison was performed.

      Oncological outcome (Table 3)

      Outcome endpoints were not reported homogenously. Some reported failure/survival rates at 2, 3 and/or 5 years and some reported crude rates at the time of last follow-up. Oncological outcomes of patients undergoing (C)RT with and without previous UFND were compared in 5 retrospective studies [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ]. The French Head and Neck Study Group (Brugere J) [
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ] and Liu et al. [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ] showed a significant positive impact of UFND on regional control (86% vs. 62%, p = 0.02 and 86% vs. 66%, p = 0.02, respectively), and Al-Mamgani et al. [
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ] described significant positive impact on survival of the group with UFND in univariate (66% vs. 42%, 3-years survival, p = 0.03) but not in multivariate analysis. However it should be noted that in the study by Liu et al. [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ] approximately half of the patients in each arm were treated with induction chemotherapy before UFND and RT and the outcome of these subgroups were not separately reported. Peters et al. [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ] (isolated nodal control: 82% vs. 96%) and Allal et al. [
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ] (local control: 81% vs. 75%, p = 0.97 and loco-regional control: 73% vs. 55%, p = 0.52) reported no statistically significant difference in the outcome comparing patients treated with and without UFND. In addition to those retrospective studies showing better oncological outcome in patients undergoing UFND, the sole prospective randomized study of Carinci et al. [
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ] confirmed the significant positive impact on survival in UFND arm (DSS: 52% vs. 29% 2-years and 29% vs. 0% 5-years; Odds ratio for DSS: 1.96 95% CI: 1.04–3.7, p = 0.037).
      Table 3Oncological outcome.
      UFND + (chemo)-radiotherapy
      Rates without any specified time point indicate the crude event rates until last follow-up.
      Author & yearLocal controlIsolated nodal controlRegional controlLRCDMFSDFSDSSOSDifferences to other arms
      Brugere
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      1991
      91%95%86% at 3 y.nor62%nornormd.: 19 mth.Isolated nodal control: 95% in UFND, 92% in post-operative RT and 80% in RT only group (p = 0.04) Nodal control at 3 y.: 86% in UFND and post-operative RT groups, 62% in RT only group (p = 0.02)

      No sign. difference in OS or distant metastasis among the three groups

      Post-operative RT group had better md. survival in supraglottic cancer: 40 mth. vs 18 mth. (UFND) vs 17 mth. (RT only group) (p = 0.03)
      Byers
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      1992
      69% at 2 y.89% at 2 y.86% at 2 y.57% at 2 y.nor51% at 5 y.nor55% at 5 y.
      Verschuur
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      1996
      80%100%100%80%73%nornor73% at 3 y.

      60% at 5 y.
      Peters
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      1996
      nor82%76%

      (80% at 2 and 3 y.)
      nornornornornorIsolated nodal control: 82% in UFND, 96% in the RT only group (no statistical comparison)
      Allal
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      1999
      81% at 3 y.92% at 3 y.78% at 3 y.73% at 3 y.nor60% at 3 y.nor37% at 3 y.No sign. differences in local (81% with UFND vs 75% with (C)RT, p = 0.97) or loco-regional control (73% with UFND vs 55%, p = 0.5) between groups
      Smeele
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      2000
      59% at 2 y.nor78% at 2 y.43% at 2 y.45% at 2 y.nor49% at 31 mth.35% at 2 y.
      Carinci
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      2001
      nornornornornornor52% at 2 y.

      26% at 5 y.
      norIn UFND and CRT alone arms, DSS in 2 and 5 y. were 52% and 26% vs 29% and 0% respectively.

      CRT alone arm had worse DSS (OR: 1.96 with 95% CI: 1.04–3.7, p = 0.037)
      Reddy
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      2005
      100%94%94%94%-94%nor100%
      D’Cruz
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      2006
      92%88%87%80% at 5 y.88%54% at 5 y.nor80% at 2 and 3 y.

      60% at 5 y.
      Cupino
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      2007
      92%100%100%95% at 2 y.91% at 2 y.88% at 2 y.

      75% at 3 y.
      nor92% at 2 and 3 y.
      Prades
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      2008
      84%94%89%82% at 2 y.nornor67% at 2 y.43% at 2 y.
      Paximadis
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      2012
      87%100%96%87%78%65% at 5 y.nor71% at 5 y.
      Liu
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      2012
      78%91%86%70%96% at 5 y.nor46% at 5 y.43% at 5 y.Regional control better in UFND arm than CRT alone (86% vs 66% p = 0.02)
      Al-Mamgani
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      2013
      84% at 3 y.nor92% at 3 y.nor80% at 3 y.64% at 3 y.78% at 3 y.66% at 3 y.Better 3 y. OS (66% vs 42%, p = 0.04) and DSS (78% vs 56%, p = 0.03) with UFND compared to (C)RT alone in univariate analysis. However only T stage remained as a significant factor in multivariate analysis
      Shenoy
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      2013
      84%nor65%nor81%70% at 5 y.nor61% at 5 y.
      CRT: concomitant chemoradiotherapy, DFS: disease-free survival, DMFS: distant metastasis-free survival, DSS: disease-specific survival, LRC: loco-regional control, md.: median, mth.: months, nor: not reported, OS: overall survival, RT: radiotherapy, UFND: up-front neck dissection, y.: years, “–”: only one arm study.
      low asterisk Rates without any specified time point indicate the crude event rates until last follow-up.

      Discussion

      Treatment of advanced loco-regional HNSCC still remains a challenge and the control of lymph node metastases is a problem of major importance. Several reasons can be advanced for this, including increased tumor load, hypoxia, or intrinsic biological features of lymph node metastases. All these can contribute to radioresistance. Therefore, surgical removal of large nodal disease before or after definitive (C)RT should hypothetically lead to a better oncological outcome, and in some studies, patients with UFND displayed improved nodal control, DSS and OS compared with those undergoing (C)RT alone. Our systematic review also provides clues that UFND treatment strategy as a part of organ-preservation protocols has less complications than salvage ND for isolated neck persistence/recurrence [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ]. Patients treated with UFND and (C)RT seem to have less serious acute toxicity than those treated with (C)RT alone. On the other hand, even if toxicity and complication rates are actually decreased with UFND, it has to be considered that surgery carries its own risks and costs. In other words, a careful ‘number needed-to-treat’ and a well-balanced cost-benefit analysis has to be performed.
      Previous high-dose radiation delivered to the neck considerably increases the risk of postoperative complications after ND [
      • Davidson B.J.
      • Newkirk K.A.
      • Harter K.W.
      • Picken C.A.
      • Cullen K.J.
      • Sessions R.B.
      Complications from planned, posttreatment neck dissections.
      ,
      • Chen Y.-J.
      • Wang C.-P.
      • Wang C.-C.
      • Jiang R.-S.
      • Lin J.-C.
      • Liu S.-A.
      Carotid blowout in patients with head and neck cancer: associated factors and treatment outcomes.
      ]. Soft tissue fibrosis and decreased vascularization are responsible for an increased risk of wound dehiscenses, infections, impaired hemostasis and higher vulnerability of large vessels leading to ruptures of the carotid artery in worst case. Of the articles included in this analysis, only two compared the postoperative complications between patients treated with UFND and those with salvage ND in case of oncological failure, showing a much higher complication rate in the latter group [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ]. Due to the fact that there were only two UFND studies comparing the surgical morbidity between these two strategies, we looked for other articles in the literature which reported complications with planned ND and salvage ND for isolated nodal recurrence after (C)RT. Complications after planned ND which is performed after (C)RT ranged from 5% to 38% [
      • Stenson K.M.
      • Haraf D.J.
      • Pelzer H.
      • et al.
      The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection.
      ,
      • Narayan K.
      • Crane C.
      • Kleid S.
      • Hughes P.
      • Peters L.
      Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?.
      ,
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Davidson B.J.
      • Newkirk K.A.
      • Harter K.W.
      • Picken C.A.
      • Cullen K.J.
      • Sessions R.B.
      Complications from planned, posttreatment neck dissections.
      ,
      • Frank D.K.
      • Hu K.S.
      • Culliney B.E.
      • et al.
      Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer.
      ,
      • Vedrine P.O.
      • Thariat J.
      • Hitier M.
      • et al.
      Need for neck dissection after radiochemotherapy? A study of the French GETTEC Group.
      ,
      • Lee H.J.
      • Zelefsky M.J.
      • Kraus D.H.
      • et al.
      Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma.
      ,
      • Robbins K.T.
      • Wong F.S.
      • Kumar P.
      • et al.
      Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer.
      ,
      • Wang S.J.
      • Wang M.B.
      • Yip H.
      • Calcaterra T.C.
      Combined radiotherapy with planned neck dissection for small head and neck cancers with advanced cervical metastases.
      ,
      • Somerset J.D.
      • Mendenhall W.M.
      • Amdur R.J.
      • Villaret D.B.
      • Stringer S.P.
      Planned postradiotherapy bilateral neck dissection for head and neck cancer.
      ,
      • Roy S.
      • Tibesar R.J.
      • Daly K.
      • et al.
      Role of planned neck dissection for advanced metastatic disease in tongue base or tonsil squamous cell carcinoma treated with radiotherapy.
      ,
      • Sewall G.K.
      • Palazzi-Churas K.L.
      • Richards G.M.
      • Hartig G.K.
      • Harari P.M.
      Planned postradiotherapy neck dissection: rationale and clinical outcomes.
      ,
      • Lango M.N.
      • Andrews G.A.
      • Ahmad S.
      • et al.
      Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis.
      ,
      • Sabatini P.R.
      • Ducic Y.
      Planned neck dissection following primary chemoradiation for advanced-stage head and neck cancer.
      ], and among articles which report detailed information, the rates of minor and major complications were between 2% and 16% and 0% and 20%, respectively [
      • Stenson K.M.
      • Haraf D.J.
      • Pelzer H.
      • et al.
      The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection.
      ,
      • Sanguineti G.
      • Califano J.
      • Stafford E.
      • et al.
      Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma.
      ,
      • Narayan K.
      • Crane C.
      • Kleid S.
      • Hughes P.
      • Peters L.
      Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?.
      ,
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Frank D.K.
      • Hu K.S.
      • Culliney B.E.
      • et al.
      Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer.
      ,
      • Vedrine P.O.
      • Thariat J.
      • Hitier M.
      • et al.
      Need for neck dissection after radiochemotherapy? A study of the French GETTEC Group.
      ,
      • Lee H.J.
      • Zelefsky M.J.
      • Kraus D.H.
      • et al.
      Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma.
      ,
      • Wang S.J.
      • Wang M.B.
      • Yip H.
      • Calcaterra T.C.
      Combined radiotherapy with planned neck dissection for small head and neck cancers with advanced cervical metastases.
      ,
      • Somerset J.D.
      • Mendenhall W.M.
      • Amdur R.J.
      • Villaret D.B.
      • Stringer S.P.
      Planned postradiotherapy bilateral neck dissection for head and neck cancer.
      ,
      • Sewall G.K.
      • Palazzi-Churas K.L.
      • Richards G.M.
      • Hartig G.K.
      • Harari P.M.
      Planned postradiotherapy neck dissection: rationale and clinical outcomes.
      ,
      • Lango M.N.
      • Andrews G.A.
      • Ahmad S.
      • et al.
      Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis.
      ,
      • Boyd T.S.
      • Harari P.M.
      • Tannehill S.P.
      • et al.
      Planned postradiotherapy neck dissection in patients with advanced head and neck cancer.
      ,
      • Mendenhall W.M.
      • Stringer S.P.
      • Amdur R.J.
      • Hinerman R.W.
      • Moore-Higgs G.J.
      • Cassisi N.J.
      Is radiation therapy a preferred alternative to surgery for squamous cell carcinoma of the base of tongue?.
      ,
      • Brizel D.M.
      • Prosnitz R.G.
      • Hunter S.
      • et al.
      Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.
      ]. These results are similar to the complication rates after UFND. Studies reporting complication rates of salvage ND explicitly describing postoperative morbidity after surgery for isolated neck recurrences without including the results of patients who underwent combined surgery for loco-regional relapse or who underwent salvage ND on initially operated and/or non-irradiated patients are rare. In studies where salvage ND was only performed for isolated neck failures (without synchronous failures of the primary), complication rates ranged from 4% to 69%, and the rates of major complications varied between 4% and 54% with a postoperative mortality rate reaching 6% [
      • Mabanta S.R.
      • Mendenhall W.M.
      • Stringer S.P.
      • Cassisi N.J.
      Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes.
      ,
      • Yen K.L.
      • Hsu L.P.
      • Sheen T.S.
      • Chang Y.L.
      • Hsu M.H.
      Salvage neck dissection for cervical recurrence of nasopharyngeal carcinoma.
      ,
      • Morgan J.E.
      • Breau R.L.
      • Suen J.Y.
      • Hanna E.Y.
      Surgical wound complications after intensive chemoradiotherapy for advanced squamous cell carcinoma of the head and neck.
      ,
      • Bland K.I.
      • Klamer T.W.
      • Polk H.C.
      • Knutson C.O.
      Isolated regional lymph node dissection: morbidity, mortality and economic considerations.
      ,
      • Amar A.
      • Chedid H.M.
      • Rapoport A.
      • et al.
      Update of assessment of survival in head and neck cancer after regional recurrence.
      ]. The rate of complications after salvage ND seems to be higher than after UFND. However, it should be noted that the percentages of post-operative complications reflect the whole population of patients who were treated with the UFND approach, whereas the rates of complications after planned ND or salvage ND belong to a selected group of cases, because these operations are not performed if the primary tumor does not respond to (C)RT and is inoperable. This makes a comparison with UFND cohorts questionable.
      Where one advantage of UFND is to avoid operating and re-irradiating a neck after a full course of (C)RT in case of persistent or recurrent nodal disease, another advantage may be the obtained level-specific mapping of nodal disease (macrometastases, extracapsular spread, presence of micrometastases) and subsequently allowing the dose and volume of RT to be tailored based on these findings. Depending on nodal disease extent, patients may receive a lower dose to the neck after UFND which removes gross disease, compared to the higher dose given to all patients primarily treated with (C)RT. Reducing the dose to the irradiated neck levels after UFND knowing the nodal status may decrease the acute and late toxicity. Unfortunately, no study focused specifically on this subject, and therefore it is not possible to argue for a clear benefit regarding decreased toxicity due to dose and volume reduction in cases of UFND. However, in spite of a lower dose (or no dose at all in case of a down-staged pN0/1 hemi-neck, without extracapsular extension), the RT volumes in the post-operative neck may on the contrary be slightly larger when compared to non-operated neck levels, especially in case of extracapsular spread. The question of whether a higher dose of RT alone or an UFND combined with a lower radiation dose is more toxic, remains unanswered. Among 2 articles in which a comparison of (C)RT with or without UFND was done, only Al-Mamgani et al. [
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ] showed a statistically significant lower rate of acute grade ⩾ 3 toxicity with UFND strategy. Grade ⩾ 3 chronic toxicity rate compared in 2 retrospective studies was similar between patient arms with and without UFND [
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ]. Series of (C)RT without UFND reported grade ⩾ 3 chronic toxicity between 0% and 55% which seems to be numerically higher than reported in the UFND patients, but any direct comparison is not possible [
      • Chan A.W.
      • Ancukiewicz M.
      • Carballo N.
      • Montgomery W.
      • Wang C.C.
      The role of postradiotherapy neck dissection in supraglottic carcinoma.
      ,
      • Frank D.K.
      • Hu K.S.
      • Culliney B.E.
      • et al.
      Planned neck dissection after concomitant radiochemotherapy for advanced head and neck cancer.
      ,
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Machtay M.
      • Moughan J.
      • Trotti A.
      • et al.
      Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • Smeele L.E.
      • Leemans C.R.
      • Reid C.B.
      • Tiwari R.
      • Snow G.B.
      Neck dissection for advanced lymph node metastasis before definitive radiotherapy for primary carcinoma of the head and neck.
      ,
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ,
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ,
      • Shenoy A.M.
      • Shiva Kumar T.
      • Prashanth V.
      • et al.
      Neck dissection followed by definitive radiotherapy for small upper aerodigestive tract squamous cell carcinoma, with advanced neck disease: an alternative treatment strategy.
      ,
      • Robbins K.T.
      • Wong F.S.
      • Kumar P.
      • et al.
      Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer.
      ,
      • Somerset J.D.
      • Mendenhall W.M.
      • Amdur R.J.
      • Villaret D.B.
      • Stringer S.P.
      Planned postradiotherapy bilateral neck dissection for head and neck cancer.
      ,
      • Mendenhall W.M.
      • Stringer S.P.
      • Amdur R.J.
      • Hinerman R.W.
      • Moore-Higgs G.J.
      • Cassisi N.J.
      Is radiation therapy a preferred alternative to surgery for squamous cell carcinoma of the base of tongue?.
      ,
      • Calais G.
      • Alfonsi M.
      • Bardet E.
      • et al.
      Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma.
      ,
      • Garden A.S.
      • Glisson B.S.
      • Ang K.K.
      • et al.
      Phase I/II trial of radiation with chemotherapy “boost” for advanced squamous cell carcinomas of the head and neck: toxicities and responses.
      ,
      • Corry J.
      • Rischin D.
      • Smith J.G.
      • et al.
      Radiation with concurrent late chemotherapy intensification (’chemoboost’) for locally advanced head and neck cancer.
      ,
      • Pletcher S.D.
      • Kaplan M.J.
      • Eisele D.W.
      • Singer M.I.
      • Quivey J.M.
      • Lee N.
      Management of cervical metastases in advanced squamous cell carcinoma of the base of tongue.
      ,
      • De Arruda F.F.
      • Puri D.R.
      • Zhung J.
      • et al.
      Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience.
      ]. Progress in the RT techniques and better understanding of dosimetric parameters of the organs at risk may positively affect toxicity related outcomes and decrease the post-(C)RT related toxicity in patients both with and without UFND [
      • Marks L.B.
      • Yorke E.D.
      • Jackson A.
      • et al.
      Use of normal tissue complication probability models in the clinic.
      ].
      It is generally accepted that, due to the very low probability of nodal persistence and the morbidity associated with ND, any planned ND before or after (C)RT in organ-preservation protocols is usually not considered for cN0–1 disease [
      • Thariat J.
      • Hamoir M.
      • Garrel R.
      • et al.
      Management of the neck in the setting of definitive chemoradiation: is there a consensus? A GETTEC study.
      ,
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ,
      • Brizel D.M.
      • Prosnitz R.G.
      • Hunter S.
      • et al.
      Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.
      ,
      • Mendenhall W.M.
      • Villaret D.B.
      • Amdur R.J.
      • Hinerman R.W.
      • Mancuso A.a.
      Planned neck dissection after definitive radiotherapy for squamous cell carcinoma of the head and neck.
      ,
      • Brown K.M.
      • Lango M.
      • Ridge J.A.
      The role of neck dissection in the combined modality therapy setting.
      ,
      • Ensley J.F.
      • Jacobs J.R.
      • Weaver A.
      • et al.
      Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck.
      ,
      • Thariat J.
      • Marcy P.-Y.
      Neck dissection and chemoradiation in head and neck cancer.
      ]. On the other edge of the spectrum, the risk of residual and viable tumor after CRT is substantial for cN2–3 disease and positively correlated to N stage and nodal size [
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Cannady S.B.
      • Lee W.T.
      • Scharpf J.
      • et al.
      Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma.
      ,
      • Cho A.H.
      • Shah S.
      • Ampil F.
      • Bhartur S.
      • Nathan C.-A.O.
      N2 disease in patients with head and neck squamous cell cancer treated with chemoradiotherapy: is there a role for posttreatment neck dissection?.
      ,
      • Bataini J.P.
      • Bernier J.
      • Jaulerry C.
      • Brunin F.
      • Pontvert D.
      • Lave C.
      Impact of neck node radioresponsiveness on the regional control probability in patients with oropharynx and pharyngolarynx cancers managed by definitive radiotherapy.
      ]. Additionally, pathologically proven viable tumor cells in lymph nodes after CRT are related with poorer survival [
      • Ganly I.
      • Bocker J.
      • Carlson D.L.
      • et al.
      Viable tumor in postchemoradiation neck dissection specimens as an indicator of poor outcome.
      ,
      • Brizel D.M.
      • Prosnitz R.G.
      • Hunter S.
      • et al.
      Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.
      ]. In the planned ND series, Cho et al. showed that 30% of the patients had persistent or recurrent nodal disease after CRT, and even if complete clinical response was achieved, Cannady et al. reported a 13.8% rate of histologically positive ND specimens [
      • Cannady S.B.
      • Lee W.T.
      • Scharpf J.
      • et al.
      Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma.
      ,
      • Cho A.H.
      • Shah S.
      • Ampil F.
      • Bhartur S.
      • Nathan C.-A.O.
      N2 disease in patients with head and neck squamous cell cancer treated with chemoradiotherapy: is there a role for posttreatment neck dissection?.
      ]. Thariat et al. showed that patients with lymph nodes bigger than 3 cm had greater than 35% isolated and overall neck recurrences within 5 years [
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ]. Especially prior to the introduction of CRT, combinations of UFND or planned ND and RT for cN2–3 disease were widely established treatment strategies [
      • Thariat J.
      • Hamoir M.
      • Garrel R.
      • et al.
      Management of the neck in the setting of definitive chemoradiation: is there a consensus? A GETTEC study.
      ].
      Concerning oncological outcomes, there were only 2 prospective trials found in our review. Carinci et al. [
      • Carinci F.
      • Cassano L.
      • Farina A.
      • et al.
      Unresectable primary tumor of head and neck: does neck dissection combined with chemoradiotherapy improve survival?.
      ] reported results with two small randomized arms: (1) UFND followed by CRT and (2) CRT alone without planned ND. Only DSS was reported (2- and 5-years: 52% and 26% vs. 29% and 0%, respectively) with univariate Cox regression analysis favoring the UFND cohort (p < 0.05). While promising, this study presents several limitations that impose careful interpretations of these results: (1) randomization methodology and stratification factors not reported; (2) non-adherence to initial inclusion criteria (not only locally-advanced HNSCC were included); (3) RT dose to the neck not reported; (4) lack of relevant outcome measures, mainly local, regional, and distant control, as well as CRT toxicity rates.
      D’Cruz et al. [
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ] reported the second prospective trial, a single-arm study which included early local (cT1-2) but regionally advanced (cN2a/b) tumors. The patients received 2-dimensional RT with doses to the primary tumor ⩾66 Gy and doses of 46–60 Gy to the neck. Patients did not receive concomitant chemotherapy. This study emphasized the feasibility of UFND with an 88% isolated regional control and LRC of 80% at 5 years. Of the remaining 13 retrospective studies, 5 contained more than one study arm, none including a planned ND strategy. Concerning the studies comparing UFND followed by (C)RT vs. (C)RT alone, 3 studies (Brugere [
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ], Liu et al. [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ], Al-Mamgani et al. [
      • Al-Mamgani A.
      • Meeuwis C.A.
      • van Rooij P.H.
      • et al.
      Node-positive hypopharyngeal cancer treated by (chemo)radiotherapy: impact of up-front neck dissection on outcome, toxicity, and quality of life.
      ]) reported statistically significant decreased oncological outcomes in the group receiving (C)RT alone (regional control: 62–66% vs. 86%; isolated regional control: 80% vs. 95%; 3 year-OS: 42% vs. 66%; 3 year-DSS: 56% vs. 78%). Peters et al. [
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ] and Allal et al. [
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ] did not show differences between the groups and advocated for UFND only if patients were fit for surgery or needed to undergo general anesthesia for other reasons (e.g. dental extractions), emphasizing that care should be taken to reduce the time between surgery and RT as it may increase the risk of treatment failure [
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Vikram B.
      • Strong E.W.
      • Shah J.P.
      • Spiro R.
      Failure in the neck following multimodality treatment for advanced head and neck cancer.
      ]. In 11 out of the 15 studies which either directly reported or allowed the calculation of isolated regional control after UFND followed by (C)RT, the rates varied between 82% and 100% [
      • Liu X.-K.
      • Li Q.
      • Zhang Q.
      • et al.
      Planned neck dissection before combined chemoradiation in organ preservation protocol for N2–N3 of supraglottic or hypopharyngeal carcinoma.
      ,
      • Paximadis P.A.
      • Christensen M.E.
      • Dyson G.
      • et al.
      Up-front neck dissection followed by concurrent chemoradiation in patients with regionally advanced head and neck cancer.
      ,
      • Byers R.M.
      • Clayman G.L.
      • Guillamondequi O.M.
      • Peters L.J.
      • Goepfert H.
      Resection of advanced cervical metastasis prior to definitive radiotherapy for primary squamous carcinomas of the upper aerodigestive tract.
      ,
      • Reddy A.N.
      • Eisele D.W.
      • Forastiere A.A.
      • Lee D.J.
      • Westra W.H.
      • Califano J.A.
      Neck dissection followed by radiotherapy or chemoradiotherapy for small primary oropharynx carcinoma with cervical metastasis.
      ,
      • Cupino A.
      • Axelrod R.
      • Anne P.R.
      • et al.
      Neck dissection followed by chemoradiotherapy for stage IV (N+) oropharynx cancer.
      ,
      • Prades J.M.
      • Timoshenko A.P.
      • Schmitt T.H.
      • et al.
      Planned neck dissection before combined chemoradiation for pyriform sinus carcinoma.
      ,
      • Peters L.J.
      • Weber R.S.
      • Morrison W.H.
      • Byers R.M.
      • Garden A.S.
      • Goepfert H.
      Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy.
      ,
      • Brugere J.
      Early pharyngolaryngeal carcinomas with palpable nodes.
      ,
      • Verschuur H.P.
      • Keus R.B.
      • Hilgers F.J.
      • Balm A.J.
      • Gregor R.T.
      Preservation of function by radiotherapy of small primary carcinomas preceded by neck dissection for extensive nodal metastases of the head and neck.
      ,
      • Allal A.
      • Dulguerov P.
      • Bieri S.
      • Lehmann W.
      • Kurtz J.M.
      A conservation approach to pharyngeal carcinoma with advanced neck disease: optimizing neck management.
      ,
      • D’cruz A.K.
      • Pantvaidya G.H.
      • Agarwal J.P.
      • et al.
      Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study.
      ]. Isolated regional control rates in the literature reporting the results of (C)RT alone with and without post-(C)RT planned ND are between 87% and 100% [
      • Narayan K.
      • Crane C.
      • Kleid S.
      • Hughes P.
      • Peters L.
      Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?.
      ,
      • Ahmed K.A.
      • Robbins K.T.
      • Wong F.
      • Salazar J.E.
      Efficacy of concomitant chemoradiation and surgical salvage for N3 nodal disease associated with upper aerodigestive tract carcinoma.
      ,
      • Ganly I.
      • Bocker J.
      • Carlson D.L.
      • et al.
      Viable tumor in postchemoradiation neck dissection specimens as an indicator of poor outcome.
      ,
      • Thariat J.
      • Ang K.K.
      • Allen P.K.
      • et al.
      Prediction of neck dissection requirement after definitive radiotherapy for head-and-neck squamous cell carcinoma.
      ,
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Lee H.J.
      • Zelefsky M.J.
      • Kraus D.H.
      • et al.
      Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma.
      ,
      • Wang S.J.
      • Wang M.B.
      • Yip H.
      • Calcaterra T.C.
      Combined radiotherapy with planned neck dissection for small head and neck cancers with advanced cervical metastases.
      ,
      • Sewall G.K.
      • Palazzi-Churas K.L.
      • Richards G.M.
      • Hartig G.K.
      • Harari P.M.
      Planned postradiotherapy neck dissection: rationale and clinical outcomes.
      ,
      • Lango M.N.
      • Andrews G.A.
      • Ahmad S.
      • et al.
      Postradiotherapy neck dissection for head and neck squamous cell carcinoma: pattern of pathologic residual carcinoma and prognosis.
      ,
      • Sabatini P.R.
      • Ducic Y.
      Planned neck dissection following primary chemoradiation for advanced-stage head and neck cancer.
      ,
      • Brizel D.M.
      • Prosnitz R.G.
      • Hunter S.
      • et al.
      Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer.
      ,
      • Cannady S.B.
      • Lee W.T.
      • Scharpf J.
      • et al.
      Extent of neck dissection required after concurrent chemoradiation for stage IV head and neck squamous cell carcinoma.
      ,
      • McHam S.A.
      • Adelstein D.J.
      • Rybicki L.A.
      • et al.
      Who merits a neck dissection after definitive chemoradiotherapy for N2–N3 squamous cell head and neck cancer?.
      ,
      • Adelstein D.J.
      • Saxton J.P.
      • Rybicki L.A.
      Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution.
      ,
      • Liauw S.L.
      • Mancuso A.A.
      • Amdur R.J.
      • et al.
      Postradiotherapy neck dissection for lymph node-positive head and neck cancer: the use of computed tomography to manage the neck.
      ] and 70% and 100% [
      • Sanguineti G.
      • Califano J.
      • Stafford E.
      • et al.
      Defining the risk of involvement for each neck nodal level in patients with early T-stage node-positive oropharyngeal carcinoma.
      ,
      • Chan A.W.
      • Ancukiewicz M.
      • Carballo N.
      • Montgomery W.
      • Wang C.C.
      The role of postradiotherapy neck dissection in supraglottic carcinoma.
      ,
      • Vongtama R.
      • Lee M.
      • Kim B.
      • et al.
      Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.
      ,
      • Grabenbauer G.G.
      • Rödel C.
      • Ernst-Stecken A.
      • et al.
      Neck dissection following radiochemotherapy of advanced head and neck cancer–for selected cases only?.
      ,
      • Garden A.S.
      • Glisson B.S.
      • Ang K.K.
      • et al.
      Phase I/II trial of radiation with chemotherapy “boost” for advanced squamous cell carcinomas of the head and neck: toxicities and responses.
      ,
      • Pletcher S.D.
      • Kaplan M.J.
      • Eisele D.W.
      • Singer M.I.
      • Quivey J.M.
      • Lee N.
      Management of cervical metastases in advanced squamous cell carcinoma of the base of tongue.
      ,
      • De Arruda F.F.
      • Puri D.R.
      • Zhung J.
      • et al.
      Intensity-modulated radiation therapy for the treatment of oropharyngeal carcinoma: the Memorial Sloan-Kettering Cancer Center experience.
      ,
      • Lopez Rodriguez M.
      • Cerezo Padellano L.
      • Martin Martin M.
      • Counago Lorenzo F.
      Neck dissection after radiochemotherapy in patients with locoregionally advanced head and neck cancer.
      ,
      • Lambrecht M.
      • Dirix P.
      • Van den Bogaert W.
      • Nuyts S.
      Incidence of isolated regional recurrence after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma.
      ,
      • Igidbashian L.
      • Fortin B.
      • Guertin L.
      • et al.
      Outcome with neck dissection after chemoradiation for N3 head-and-neck squamous cell carcinoma.
      ,
      • Yovino S.
      • Settle K.
      • Taylor R.
      • et al.
      Patterns of failure among patients with squamous cell carcinoma of the head and neck who obtain a complete response to chemoradiotherapy.
      ], respectively. Unfortunately, any direct comparison between these treatment strategies and oncological results is not possible. In contrast to the good results with planned ND, the outcome of isolated neck recurrences are poor and the efficacy of surgery is correlated with the stage of recurrence [
      • Mabanta S.R.
      • Mendenhall W.M.
      • Stringer S.P.
      • Cassisi N.J.
      Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes.
      ,
      • Van der Putten L.
      • van den Broek G.B.
      • de Bree R.
      • et al.
      Effectiveness of salvage selective and modified radical neck dissection for regional pathologic lymphadenopathy after chemoradiation.
      ,
      • Goodwin W.J.
      Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means?.
      ]. Mabanta et al. [
      • Mabanta S.R.
      • Mendenhall W.M.
      • Stringer S.P.
      • Cassisi N.J.
      Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes.
      ] reported the outcome of 51 patients with isolated neck persistence/recurrence after RT alone. Thirty-five percent of these cases had unresectable disease, and in those who underwent salvage ND, the 5-year regional control, DSS and OS after salvage was only 9%, 10% and 10%, respectively. More recently, the series of van der Putten et al. [
      • Van der Putten L.
      • van den Broek G.B.
      • de Bree R.
      • et al.
      Effectiveness of salvage selective and modified radical neck dissection for regional pathologic lymphadenopathy after chemoradiation.
      ] described the outcome of 129 patients with regional residual or recurrent disease after initial CRT. Of these cases, 53% were considered inoperable. The 5-year regional control rate of the patients undergoing salvage ND was 79% and the OS 36%.
      There is a growing body of evidence supporting the reliability of the clinical response assessment after CRT, and this has probably caused a shift of preference toward abandoning planned ND in cases of complete response. A critical appraisal of the literature provided here also gives some hints suggesting several potential advantages of UFND as a part of (C)RT organ-preservation protocols when compared to (C)RT alone.
      Several limitations in our findings must be acknowledged. First, most study designs were retrospective. Second, some studies belong to an era prior to CRT, thus comparing UFND versus RT alone. Third, the study populations encompass a multitude of primary tumor sites and disease stages, with diagnostic and therapeutic procedures that are heterogeneous partly due to the large time span, but also due to different inter-institutional approaches. Additionally, current knowledge would impose to stratify patients according to Human Papilloma Virus status in order to obtain accurate interpretations in this subpopulation of patients. Finally, a meta-analysis could not be performed due to lack of randomized data, heterogeneity in outcome measures and reporting methodology. Despite these limitations, we believe that this first review about UFND provides clues supporting the evaluation of this strategy in a well-designed methodological basis.

      Conclusions

      Some of the few comparative studies suggest possible benefits of UFND approach in the (C)RT organ-preservation setting in terms of reduced acute toxicity and favorable oncological outcome, but the level of evidence remains low. Due to heterogeneity in study characteristics and reporting methodology, performing a meta-analysis is not reasonable. Well-designed randomized controlled trials analyzing benefits of outcome and cost-effectiveness are needed to further assess the efficacy of (C)RT with and without UFND.

      Funding

      None.

      Conflict of interest statement

      All authors declare no conflicts of interest.

      Appendix A. Supplementary data

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