Acta Oto-Laryngologica

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A Nordic survey on the management of head and neck CUP

Lovisa Farnebo, Göran Laurell & Antti Mäkitie

To cite this article: Lovisa Farnebo, Göran Laurell & Antti Mäkitie (2016) A Nordic survey on the management of head and neck CUP, Acta Oto-Laryngologica, 136:11, 1159-1163, DOI: 10.1080/00016489.2016.1193894

To link to this article: http://dx.doi.org/10.1080/00016489.2016.1193894

© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

Published online: 16 Jun 2016.

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Download by: [University of ] Date: 22 November 2016, At: 04:54 ACTA OTO-LARYNGOLOGICA, 2016 VOL. 136, NO. 11, 1159–1163 http://dx.doi.org/10.1080/00016489.2016.1193894

RESEARCH ARTICLE A Nordic survey on the management of head and neck CUP

Lovisa Farneboa , Goran€ Laurellb and Antti M€akitiec,d aDepartment of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden; bDepartment of Clinical Sciences, ENT, Uppsala University, Uppsala, Sweden; cDepartment of Otorhinolaryngology, University of Helsinki and Helsinki University Hospital, Helsinki, ; dDivision of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

ABSTRACT ARTICLE HISTORY Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies Received 10 April 2016 both between centres within and also between the Nordic countries. This study contributes to a con- Revised 2 May 2016 tinuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP Accepted 3 May 2016 patients. KEYWORDS Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic Cancer of unknown origin; procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a follow up; multidisciplinary rather homogeneous population. tumour board meeting; Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries. PET-CT Results: Four of the five Nordic countries use either national guidelines or specific protocols when han- dling HNCUP. The main diagnostic tools are PET-CT, fine needle aspiration, endoscopic evaluation with biopsies, and most often bilateral tonsillectomy. At 21 of 22 university hospitals the treatment decision is made at a multidisciplinary conference. Three of seven Swedish centres use only radiotherapy or che- moradiotherapy to treat Nþ HNCUP patients. Robotic surgery for biopsy of the tongue base is begin- ning to become an alternative to targeted biopsies in Sweden and Finland. Narrow Band Imaging is used only in Finland.

Introduction and Finland). The recommendation is that the diagnostic work-up should include both PET-CT and panendoscopy The definition of Head and Neck Cancer of Unknown with biopsies, including bilateral tonsillectomy [2,6]. Such an Primary (HNCUP) is the presence of a cervical lymph node action may offer the greatest likelihood of successfully identi- metastasis, for which therapy will be initiated even though fying an occult primary tumour. However, the availability of there is no specific evidence of a primary tumour. Extensive PET-CT varies, as do the guidelines to use it. clinical and radiological examinations are typically under- Therapeutic approaches vary between centres, and treat- taken before initiating treatment of HNCUP. The incidence of HNCUP varies between 3–7% of all neck ment modalities include surgery (lymph node excision or lumps [1]. Many patients with an occult neck lump initially neck dissection) with or without post-operative radiotherapy; diagnosed as a HNCUP are later identified with a primary radiotherapy, alone or in combination with chemotherapy; tumour. Waltonen et al. [2] found that nearly half of all pri- and radiotherapy, followed by surgery. In the early stage mary tumours could be located using PET-CT and endoscopy. (N1), neck dissection and radiotherapy seem to have similar A more recent report suggested that males constitute 72% of efficacy, whereas more advanced cases (N2, N3) necessitate a all cases, the median age at onset being 55 years combination of modalities [6]. One retrospective study con- (range ¼ 42–87 years) [3]. Lymph node metastases located in cluded that radiotherapy after neck dissection influenced the the supraclavicular fossa are frequently found to be of infra- overall survival [7], while another study suggested that IMRT clavicular origin. Fine needle aspiration cytology and modern was the most beneficial radiotherapeutic approach [8]. molecular diagnostics have improved the assessment of cancer Mistry et al. [9] reported that the overall 5-year survival was of unknown primary. Accurate cytological diagnosis of better for HNCUP patients than for those with a known pri- HNCUP is essential when choosing treatment modality, and mary of comparable nodal stage. The overall 5-year survival may become increasingly important in the HPV era [4,5]. rate for the HNCUP group was found to be 55%.In It has been recognized that the diagnostic and treatment line with this, another study reported the 5-year survival rate modalities for HNCUP cases differ, and the present study is to be poorer among HNCUP patients where a primary the first attempt to systematically assess these differences in tumour was later detected, when compared with patients the Nordic countries (Iceland, Norway, Denmark, Sweden, having a persistent unknown primary (22% vs 52%).

CONTACT Lovisa Farnebo, MD, PhD [email protected] Department of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Linkoping€ University, SE-58185 Link€oping, Sweden ß 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, dis- tribution, and reproduction in any medium, provided the original work is properly cited. 1160 L. FARNEBO ET AL.

Figure 1. Map showing all the university hospitals managing HNCUP included in this study; (1) Reykjavik, (2) Oslo, (3) Bergen, (4) Trondheim, (5) Tromsoe, (6) Aalborg, (7) Aarhus, (8) Odense, (9) Herlev, (10) Copenhagen, (11) Lund, (12) , (13) Link€oping, (14) Orebro,€ (15) Stockholm, (16) Uppsala, (17) Umeå, (18) Helsinki, (19) Turku, (20) , (21) Kuopio, and (22) Oulu.

Significant prognostic factors in HNCUP were M-class, questionnaire was revised accordingly by the authors. It now smoking, alcohol consumption, and tonsillectomy [6]. comprised four parts (General information (2 questions), The aim of this study was to compare diagnostic proce- Diagnostic procedures for HNCUP (11 questions), Treatment dures for and treatment of HNCUP at the head and neck of HNCUP (15 questions), Follow-up of HNCUP (3 ques- cancer centres of university hospitals in the five Nordic tions)). Early in 2015 the revised questionnaire was sent to countries. all university hospitals in the Nordic countries (Figure 1), representing a total population of 25 million people. All university hospitals in Iceland (1), Sweden (7), Materials and methods Norway (4), and Finland (5) kindly responded to the ques- A multiple-choice questionnaire was designed in English by tionnaire. Denmark referred to their national guidelines for the three authors, based on clinical experience and on appro- HNCUP (www.DAHANCA.oncology.dk/Brows_Web_ priate current literature. The questionnaire was designed to Guidelines 2013), and a senior oncologist representing identify differences in diagnostic and treatment protocols DAHANCA completed the questionnaire accordingly. between the Nordic university hospitals. Questions regarding outcome data were not included in this survey. The question- Results naire was first tested at the Finnish university hospitals. Consequently, physicians in Finland were used as a pilot The management of HNCUP in Iceland and Sweden fol- group in order to fine-tune the questions. After collecting lowed a specific protocol based on local routines regarding the comments from the Finnish university hospitals, the diagnostic procedure and treatment. Finland had national ACTA OTO-LARYNGOLOGICA 1161

Table 1. Diagnostic procedures. Table 2. Treatment. n % n % Imaging modality N1 PET/CT 14 64 Treatment CT 7 32 Surgery 5 23 MRI 1 5 RT 2 9 Cytological method (needle aspiration) CRT 7 32 Fine 22 100 Surgery þ RT 1 5 Middle 0 0 Surgery þ CRT 7 32 Thick 0 0 Radiotherapy dose (Gy) Sites included for scopy 50–70 16 72 B, E, H, L 11 50 0ther 1 5 H, L 11 50 No RT 5 23 Biopsies Radiotherapy of the neck* N, TB, T 17 77 Ipsilateral 5 24 N, TB 2 9 Bilateral 11 52 TB, T 2 9 No RT 5 24 T15N2 Tonsillectomy Treatment Unilateral 2 9 Surgery — — Bilateral 17 77 RT 2 9 Bilateral in selected cases 3 14 CRT 2 9 Robotic surgery Surgery þ RT 7 32 Yes 5 23 Surgery þ CRT 11 50 No 17 77 Radiotherapy dose (Gy) Assessment under anaesthesia 50–70 21 95 Palpation 22 100 0ther 1 5 Narrow band imaging 5 23 Radiotherapy of the neck* Toluidine blue 0 0 Ipsilateral 4 19 B: bronchoscopy; E: esophagoscopy; H: hypopharyngoscopy; Bilateral 17 81 L: laryngoscopy; N: nasopharynx; TB: tongue base; T: tonsil. N3 Treatment Surgery — — guidelines for the treatment of head and neck cancer, but no RT 1 5 specific protocol for the diagnostics of HNCUP. In CRT 2 9 Surgery þ RT 7 32 Denmark, all centres applied the same national guidelines, Surgery þ CRT 12 54 while, in Norway, two university hospitals used local proto- Radiotherapy dose (Gy) 50–70 22 100 cols, but no specific protocol was followed at the remaining Radiotherapy of the neck* two centres. Patients were discussed at weekly Ipsilateral 2 10 Multidisciplinary Tumour Board Meetings (MTBM) at all Bilateral 19 90 sites except in Iceland. *Data missing from one centre. In Sweden, two out of seven centres performed PET-CT (Neck-Chest) as a primary imaging modality, and the In addition, tonsillectomy was performed either ipsi- or bilat- remaining centres performed conventional CT (Neck-Chest) erally at all centres. Most centres in Denmark (5/5), Sweden first. PET-CT was applied in all cases of HNCUP in (6/7), Norway (2/4), and Finland (4/5) performed bilateral Denmark and Finland. In Iceland, PET-CT was unavailable. tonsillectomy as a standard procedure. The remaining five In Norway two centres performed PET-CT in selected cases, centres performed bilateral tonsillectomy only in selected whereas the others used CT or MRI as their first choice of cases. imaging (Table 1). Robotic surgery for biopsy of the tongue base was begin- Fine needle aspiration of the cervical mass was reportedly ning to become an alternative to targeted biopsies in Sweden carried out at all the participating centres in the Nordic and Finland; the other countries had not yet introduced this countries. The relation to HPV positivity was evaluated at all procedure into their protocol. In Finland, Narrow Band centres (except in Iceland), with either p16 or PCR tech- Imaging was used during endoscopy to improve the informa- nique. EBV analysis was not a routine procedure in any of tion where a biopsy should be taken. the Nordic countries. In Sweden, three centres did not perform neck dissections Panendoscopy, including bronchoscopy, esophagoscopy, in Nþ HNCUP patients; instead, they used solely radiother- hypopharyngoscopy, and laryngoscopy, was performed at all apy or chemoradiotherapy. All other university hospitals centres in Finland. In Iceland and Denmark, selective endos- used radiotherapy or chemoradiotherapy combined with copies were performed, including hypopharyngoscopy and neck dissection (Table 2). laryngoscopy. In Sweden and Norway, local routines were Concerning follow-up, there was a disparity between followed. Twenty-one of 22 centres performed endoscopic Finland and the other Nordic countries. In Finland, patients procedures after the primary imaging. treated for HNCUP were always monitored by the ENT sur- Biopsy samples to detect a primary tumour were taken geon, whereas the other Nordic countries most often used a from the tongue base, and epipharynx at all centres in combined approach with visits alternatingly to ENT physi- Denmark and Sweden. In Finland, Norway, and Iceland, cians and oncologists. All Nordic patients were followed up biopsies were taken according to their local routines. for 5 years after treatment. Most patients were initially seen 1162 L. FARNEBO ET AL. by the primary treating centres, although a combination fol- treatment decision and optimization of patient care. Nguyen low-up was often organized, where every second visit was et al. [15] conclude that, when all team members of the performed by the referring hospital. MTBM take part in the treatment decision-making, it will be based on performance status rather than inherent bias due to age or perceived comorbidity. It should be noted that all the Discussion Nordic university hospitals except one used MTBM as stand- The initiative to undertake this study was the lack of inter- ard routine. nationally accepted guidelines for diagnostic procedures and All countries except one either followed a specific protocol treatment specifications for HNCUP patients. The study or national guidelines for the management of HNCUP. Only was carried out at a tertiary hospital level in northern three centres treated patients with single modality radiother- Europe. The five Nordic countries combined have a rather apy/chemoradiotherapy for Nþ necks, whereas the majority homogeneous population ( 25 million) regarding socioeco- combined neck dissection with radiotherapy/chemoradiother- nomic and health-related factors. The countries’ healthcare apy (86%). systems are similar, but there are still no unified treatment The great majority of previous studies are based on retro- protocols between them to tackle HNCUP. It, therefore, spective data. Shoushtari et al. [16] found that pre-operative seemed justified to evaluate the differences in existing IMRT (50–56 Gy) followed by neck dissection gave excellent % guidelines in this field. We chose to undertake the present overall and disease-free survival in N1–N2a disease (100 ). investigation, specifically the management of HNCUP, as Furthermore, they found that patients with N2b–N3 disease, % ¼ this would merely demonstrate the differences in guidelines with a significantly lower survival rate (66.7 , p 0.017), benefitted from concurrent chemotherapy, targeted thera- between the centres and not, for example, their availability peutic agents or accelerated radiotherapy regimens, in add- to use the various advanced reconstructive or oncological ition to surgery. Cuaron et al. [17], however, found that techniques. conventional radiotherapy produced excellent locoregional It is noteworthy that this survey covered all 22 university control of HNCUP with acceptably low levels of late toxicity. hospitals in the five Nordic countries treating these patients. Chen et al. [18] reported that concurrent chemoradiotherapy This collaborative effort was made possible by the existing was associated with significantly increased toxicity without membership network of the Scandinavian Society for Head definite benefit in overall survival or locoregional control in and Neck Oncology. The Society strives to promote collabor- the treatment of HNCUP. It has been suggested that post- ation between head and neck surgeons and oncologists in the

operative radiotherapy does not influence the rate of neck Nordic countries, to stimulate multi-centre studies, and to relapse (p ¼ 0.72), although when Issing et al. [7] compared assist any advances toward unified treatment guidelines. radiotherapy alone with neck dissection plus post-operative In the present study 14 of the 22 centres (64%) used radiotherapy, they found a significantly improved survival PET-CT as a primary imaging modality, although even PET- rate in patients who underwent a diagnostic bilateral tonsil- CT is limited in its ability to detect small tumours. In a lectomy in addition to combined modality treatment. We meta-analysis comprising 13 studies, the sensitivity and spe- speculate that the reason why some centres do not perform cificity values of PET-CT were 0.84 and 0.96, respectively, neck dissection could be that the occult primary tumour whereas those of conventional imaging were 0.63 and 0.96, often arises in the oropharyngeal region, which is included indicating that PET-CT may be more sensitive than conven- in the radiotherapy field. Furthermore, the probability of an tional imaging [10]. However, PET-CT may have a problem HPV-positive tumour in this region is high [5] and the prog- with high false-positivity rates, due to relatively low specifi- nostic implications of HPV-positive nodes in HNCUP are city, which is why multiple biopsies from suspicious sites are similar to those in oropharyngeal primary cancers [4]. When recommended even after PET-CT [11]. Furthermore, it is radiotherapy or chemo-radiotherapy is given, a small occult important that treatment initiation is not delayed due to primary tumour will be cured, and most likely never even be lacking availability of PET-CT [12]. detected during the follow-up. For this reason, some centres Five centres in Sweden and Finland used robotic surgery maintain a conservative approach to surgery, sparing the to improve the quality of biopsies from the tongue base. In a patient from surgical side-effects, even though a selective study by Karni et al. [13] on the use of transoral laser micro- neck dissection is associated with little post-operative surgery, a 94% primary tumour detection rate was demon- morbidity. strated, suggesting better specificity than with targeted In Denmark, all centres have consented to follow their biopsies. To date, only Finnish university hospitals use national guidelines. During this study, Sweden published its Narrow Band Imaging on a regular basis in order to opti- first national guidelines (Huvud och halscancer – Nationellt mize the quality of the biopsy. In a recent review, Koivunen vårdprogram 2015 Aug), although there is some scope for et al. [14] reported an increased detection rate of the primary local variation in the diagnostic work-up and treatment rec- tumour from 80% to 90%, following the introduction of ommendations. In Finland all university hospitals follow Narrow Band Imaging technique, combined with PET-CT national guidelines for the treatment of head and neck can- and trans-oral diagnostic procedures. Together, these studies cer, but there are obvious variations regarding certain details, add valuable information to a growing body of evidence that as could be observed for the diagnosis of HNCUP in the cur- new diagnostic tools can improve diagnostic accuracy for pri- rent study. The other Nordic countries adapt their manage- mary tumours. MTBM is regarded as the gold standard for ment according to local traditions. ACTA OTO-LARYNGOLOGICA 1163

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