Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ioto20
Download by: [85.228.192.112] Date: 07 December 2016, At: 10:38
Acta Oto-Laryngologica
ISSN: 0001-6489 (Print) 1651-2251 (Online) Journal homepage: http://www.tandfonline.com/loi/ioto20
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.
Submit your article to this journal
Article views: 168
View related articles
RESEARCH ARTICLE
A Nordic survey on the management of head and neck CUP
Lovisa Farneboa , G€oran Laurellb and Antti M€akitiec,d
a
Department of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden;
b
Department of Clinical Sciences, ENT, Uppsala University, Uppsala, Sweden;cDepartment of Otorhinolaryngology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;dDivision of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
ABSTRACT
Conclusion: The management of Head and Neck Cancer of Unknown Primary (HNCUP) patients varies both between centres within and also between the Nordic countries. This study contributes to a con-tinuing discussion of how to improve the accuracy of diagnosis and quality of treatment of HNCUP patients.
Objectives: The initiative for this study was based on the lack of common guidelines for diagnostic procedures and for treatment of HNCUP patients in the Nordic countries constituting a region having a rather homogeneous population.
Method: A structured questionnaire was sent to all university hospitals in the five Nordic countries. 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.
ARTICLE HISTORY
Received 10 April 2016 Revised 2 May 2016 Accepted 3 May 2016
KEYWORDS
Cancer of unknown origin; follow up; multidisciplinary tumour board meeting; PET-CT
Introduction
The definition of Head and Neck Cancer of Unknown Primary (HNCUP) is the presence of a cervical lymph node metastasis, for which therapy will be initiated even though there is no specific evidence of a primary tumour. Extensive clinical and radiological examinations are typically under-taken before initiating treatment of HNCUP.
The incidence of HNCUP varies between 3–7% of all neck lumps [1]. Many patients with an occult neck lump initially diagnosed as a HNCUP are later identified with a primary tumour. Waltonen et al. [2] found that nearly half of all pri-mary tumours could be located using PET-CT and endoscopy. A more recent report suggested that males constitute 72% of all cases, the median age at onset being 55 years (range ¼ 42–87 years) [3]. Lymph node metastases located in the supraclavicular fossa are frequently found to be of infra-clavicular origin. Fine needle aspiration cytology and modern molecular diagnostics have improved the assessment of cancer of unknown primary. Accurate cytological diagnosis of HNCUP is essential when choosing treatment modality, and may become increasingly important in the HPV era [4,5].
It has been recognized that the diagnostic and treatment modalities for HNCUP cases differ, and the present study is the first attempt to systematically assess these differences in the Nordic countries (Iceland, Norway, Denmark, Sweden,
and Finland). The recommendation is that the diagnostic work-up should include both PET-CT and panendoscopy with biopsies, including bilateral tonsillectomy [2,6]. Such an action may offer the greatest likelihood of successfully identi-fying an occult primary tumour. However, the availability of PET-CT varies, as do the guidelines to use it.
Therapeutic approaches vary between centres, and treat-ment modalities include surgery (lymph node excision or neck dissection) with or without post-operative radiotherapy; radiotherapy, alone or in combination with chemotherapy; and radiotherapy, followed by surgery. In the early stage (N1), neck dissection and radiotherapy seem to have similar efficacy, whereas more advanced cases (N2, N3) necessitate a combination of modalities [6]. One retrospective study con-cluded that radiotherapy after neck dissection influenced the overall survival [7], while another study suggested that IMRT was the most beneficial radiotherapeutic approach [8]. Mistry et al. [9] reported that the overall 5-year survival was better for HNCUP patients than for those with a known pri-mary of comparable nodal stage. The overall 5-year survival rate for the HNCUP group was found to be 55%. In line with this, another study reported the 5-year survival rate to be poorer among HNCUP patients where a primary tumour was later detected, when compared with patients having a persistent unknown primary (22% vs 52%).
CONTACTLovisa Farnebo, MD, PhD lovisa.farnebo@regionostergotland.se Department of Otorhinolaryngology, Department of Clinical and Experimental Medicine, Link€oping 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.
Significant prognostic factors in HNCUP were M-class, smoking, alcohol consumption, and tonsillectomy [6].
The aim of this study was to compare diagnostic proce-dures for and treatment of HNCUP at the head and neck cancer centres of university hospitals in the five Nordic countries.
Materials and methods
A multiple-choice questionnaire was designed in English by the three authors, based on clinical experience and on appro-priate current literature. The questionnaire was designed to identify differences in diagnostic and treatment protocols between the Nordic university hospitals. Questions regarding outcome data were not included in this survey. The question-naire was first tested at the Finnish university hospitals. Consequently, physicians in Finland were used as a pilot group in order to fine-tune the questions. After collecting the comments from the Finnish university hospitals, the
questionnaire was revised accordingly by the authors. It now comprised four parts (General information (2 questions), Diagnostic procedures for HNCUP (11 questions), Treatment of HNCUP (15 questions), Follow-up of HNCUP (3 ques-tions)). Early in 2015 the revised questionnaire was sent to 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), Norway (4), and Finland (5) kindly responded to the ques-tionnaire. Denmark referred to their national guidelines for HNCUP (www.DAHANCA.oncology.dk/Brows_Web_ Guidelines 2013), and a senior oncologist representing DAHANCA completed the questionnaire accordingly.
Results
The management of HNCUP in Iceland and Sweden fol-lowed a specific protocol based on local routines regarding diagnostic procedure and treatment. Finland had national
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) Gothenburg, (13) Link€oping, (14) €Orebro, (15) Stockholm, (16) Uppsala, (17) Umeå, (18) Helsinki, (19) Turku, (20) Tampere, (21) Kuopio, and (22) Oulu.
guidelines for the treatment of head and neck cancer, but no specific protocol for the diagnostics of HNCUP. In Denmark, all centres applied the same national guidelines, while, in Norway, two university hospitals used local proto-cols, but no specific protocol was followed at the remaining two centres. Patients were discussed at weekly Multidisciplinary Tumour Board Meetings (MTBM) at all sites except in Iceland.
In Sweden, two out of seven centres performed PET-CT (Neck-Chest) as a primary imaging modality, and the remaining centres performed conventional CT (Neck-Chest) first. PET-CT was applied in all cases of HNCUP in Denmark and Finland. In Iceland, PET-CT was unavailable. In Norway two centres performed PET-CT in selected cases, whereas the others used CT or MRI as their first choice of imaging (Table 1).
Fine needle aspiration of the cervical mass was reportedly carried out at all the participating centres in the Nordic countries. The relation to HPV positivity was evaluated at all centres (except in Iceland), with either p16 or PCR tech-nique. EBV analysis was not a routine procedure in any of the Nordic countries.
Panendoscopy, including bronchoscopy, esophagoscopy, hypopharyngoscopy, and laryngoscopy, was performed at all centres in Finland. In Iceland and Denmark, selective endos-copies were performed, including hypopharyngoscopy and laryngoscopy. In Sweden and Norway, local routines were followed. Twenty-one of 22 centres performed endoscopic procedures after the primary imaging.
Biopsy samples to detect a primary tumour were taken from the tongue base, and epipharynx at all centres in Denmark and Sweden. In Finland, Norway, and Iceland, biopsies were taken according to their local routines.
In addition, tonsillectomy was performed either ipsi- or bilat-erally at all centres. Most centres in Denmark (5/5), Sweden (6/7), Norway (2/4), and Finland (4/5) performed bilateral tonsillectomy as a standard procedure. The remaining five centres performed bilateral tonsillectomy only in selected cases.
Robotic surgery for biopsy of the tongue base was begin-ning to become an alternative to targeted biopsies in Sweden and Finland; the other countries had not yet introduced this procedure into their protocol. In Finland, Narrow Band Imaging was used during endoscopy to improve the informa-tion where a biopsy should be taken.
In Sweden, three centres did not perform neck dissections in Nþ HNCUP patients; instead, they used solely radiother-apy or chemoradiotherradiother-apy. All other university hospitals used radiotherapy or chemoradiotherapy combined with neck dissection (Table 2).
Concerning follow-up, there was a disparity between Finland and the other Nordic countries. In Finland, patients treated for HNCUP were always monitored by the ENT sur-geon, whereas the other Nordic countries most often used a combined approach with visits alternatingly to ENT physi-cians and oncologists. All Nordic patients were followed up for 5 years after treatment. Most patients were initially seen
Table 1.Diagnostic procedures.
n %
Imaging modality
PET/CT 14 64
CT 7 32
MRI 1 5
Cytological method (needle aspiration)
Fine 22 100
Middle 0 0
Thick 0 0
Sites included for scopy
B, E, H, L 11 50 H, L 11 50 Biopsies N, TB, T 17 77 N, TB 2 9 TB, T 2 9 T 1 5 Tonsillectomy Unilateral 2 9 Bilateral 17 77
Bilateral in selected cases 3 14 Robotic surgery
Yes 5 23
No 17 77
Assessment under anaesthesia
Palpation 22 100
Narrow band imaging 5 23 Toluidine blue 0 0 B: bronchoscopy; E: esophagoscopy; H: hypopharyngoscopy; L: laryngoscopy; N: nasopharynx; TB: tongue base; T: tonsil.
Table 2. Treatment. n % N1 Treatment Surgery 5 23 RT 2 9 CRT 7 32 Surgeryþ RT 1 5 Surgeryþ CRT 7 32 Radiotherapy dose (Gy)
50–70 16 72
0ther 1 5
No RT 5 23
Radiotherapy of the neck*
Ipsilateral 5 24 Bilateral 11 52 No RT 5 24 N2 Treatment Surgery — — RT 2 9 CRT 2 9 Surgeryþ RT 7 32 Surgeryþ CRT 11 50 Radiotherapy dose (Gy)
50–70 21 95
0ther 1 5
Radiotherapy of the neck*
Ipsilateral 4 19 Bilateral 17 81 N3 Treatment Surgery — — RT 1 5 CRT 2 9 Surgeryþ RT 7 32 Surgeryþ CRT 12 54 Radiotherapy dose (Gy)
50–70 22 100
Radiotherapy of the neck*
Ipsilateral 2 10
Bilateral 19 90
by the primary treating centres, although a combination fol-low-up was often organized, where every second visit was performed by the referring hospital.
Discussion
The initiative to undertake this study was the lack of inter-nationally accepted guidelines for diagnostic procedures and treatment specifications for HNCUP patients. The study was carried out at a tertiary hospital level in northern Europe. The five Nordic countries combined have a rather homogeneous population ( 25 million) regarding socioeco-nomic and health-related factors. The countries’ healthcare systems are similar, but there are still no unified treatment protocols between them to tackle HNCUP. It, therefore, seemed justified to evaluate the differences in existing guidelines in this field. We chose to undertake the present investigation, specifically the management of HNCUP, as this would merely demonstrate the differences in guidelines between the centres and not, for example, their availability to use the various advanced reconstructive or oncological techniques.
It is noteworthy that this survey covered all 22 university hospitals in the five Nordic countries treating these patients. This collaborative effort was made possible by the existing membership network of the Scandinavian Society for Head and Neck Oncology. The Society strives to promote collabor-ation between head and neck surgeons and oncologists in the Nordic countries, to stimulate multi-centre studies, and to assist any advances toward unified treatment guidelines.
In the present study 14 of the 22 centres (64%) used CT as a primary imaging modality, although even PET-CT is limited in its ability to detect small tumours. In a meta-analysis comprising 13 studies, the sensitivity and spe-cificity values of PET-CT were 0.84 and 0.96, respectively, whereas those of conventional imaging were 0.63 and 0.96, indicating that PET-CT may be more sensitive than conven-tional imaging [10]. However, PET-CT may have a problem with high false-positivity rates, due to relatively low specifi-city, which is why multiple biopsies from suspicious sites are recommended even after PET-CT [11]. Furthermore, it is important that treatment initiation is not delayed due to lacking availability of PET-CT [12].
Five centres in Sweden and Finland used robotic surgery to improve the quality of biopsies from the tongue base. In a study by Karni et al. [13] on the use of transoral laser micro-surgery, a 94% primary tumour detection rate was demon-strated, suggesting better specificity than with targeted biopsies. To date, only Finnish university hospitals use Narrow Band Imaging on a regular basis in order to opti-mize the quality of the biopsy. In a recent review, Koivunen et al. [14] reported an increased detection rate of the primary tumour from 80% to 90%, following the introduction of Narrow Band Imaging technique, combined with PET-CT and trans-oral diagnostic procedures. Together, these studies add valuable information to a growing body of evidence that new diagnostic tools can improve diagnostic accuracy for pri-mary tumours. MTBM is regarded as the gold standard for
treatment decision and optimization of patient care. Nguyen et al. [15] conclude that, when all team members of the 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 Nordic university hospitals except one used MTBM as stand-ard routine.
All countries except one either followed a specific protocol or national guidelines for the management of HNCUP. Only three centres treated patients with single modality radiother-apy/chemoradiotherapy for Nþ necks, whereas the majority combined neck dissection with radiotherapy/chemoradiother-apy (86%).
The great majority of previous studies are based on retro-spective data. Shoushtari et al. [16] found that pre-operative IMRT (50–56 Gy) followed by neck dissection gave excellent overall and disease-free survival in N1–N2a disease (100%). Furthermore, they found that patients with N2b–N3 disease, with a significantly lower survival rate (66.7%, p ¼ 0.017), benefitted from concurrent chemotherapy, targeted thera-peutic agents or accelerated radiotherapy regimens, in add-ition to surgery. Cuaron et al. [17], however, found that conventional radiotherapy produced excellent locoregional control of HNCUP with acceptably low levels of late toxicity. Chen et al. [18] reported that concurrent chemoradiotherapy was associated with significantly increased toxicity without definite benefit in overall survival or locoregional control in the treatment of HNCUP. It has been suggested that post-operative radiotherapy does not influence the rate of neck relapse (p ¼ 0.72), although when Issing et al. [7] compared radiotherapy alone with neck dissection plus post-operative radiotherapy, they found a significantly improved survival rate in patients who underwent a diagnostic bilateral tonsil-lectomy in addition to combined modality treatment. We speculate that the reason why some centres do not perform neck dissection could be that the occult primary tumour often arises in the oropharyngeal region, which is included in the radiotherapy field. Furthermore, the probability of an HPV-positive tumour in this region is high [5] and the prog-nostic implications of HPV-positive nodes in HNCUP are similar to those in oropharyngeal primary cancers [4]. When radiotherapy or chemo-radiotherapy is given, a small occult primary tumour will be cured, and most likely never even be detected during the follow-up. For this reason, some centres maintain a conservative approach to surgery, sparing the patient from surgical side-effects, even though a selective neck dissection is associated with little post-operative morbidity.
In Denmark, all centres have consented to follow their national guidelines. During this study, Sweden published its first national guidelines (Huvud och halscancer – Nationellt vårdprogram 2015 Aug), although there is some scope for local variation in the diagnostic work-up and treatment rec-ommendations. In Finland all university hospitals follow national guidelines for the treatment of head and neck can-cer, but there are obvious variations regarding certain details, as could be observed for the diagnosis of HNCUP in the cur-rent study. The other Nordic countries adapt their manage-ment according to local traditions.
This survey contributes to an on-going discussion intended to improve the quality of diagnosis and treatment of HNCUP patients. In conclusion, the main diagnostic tools currently used are PET-CT, fine needle aspiration, and endo-scopic evaluation with biopsies from the nasopharynx, tongue base, and bilateral tonsillectomy. Treatment modal-ities include radiotherapy/chemoradiotherapy or neck dissec-tion combined with radiotherapy/chemoradiotherapy. The addition of chemotherapy is generally given when the patient is fit to receive it and below 70 years of age.
The current study has established a suitable network and platform in northern Europe based on a population exceed-ing 25 million. Such a multi-centre network can be used to compare survival data according to the given treatment, and thereby facilitate future evaluation of survival differences between the two major treatment groups: moradiotherapy, or surgery combined with radiotherapy/che-moradiotherapy. Future multi-centre studies using this starting point may hopefully improve our understanding of the diagnostic tools, and how to manage HNCUP. Moreover, this Nordic network could be used to establish common guidelines for follow-up of patients with HNCUP, regarding recurrence, late detection of primary tumours, and treatment squealae.
Acknowledgements
We gratefully acknowledge all colleagues in the Nordic countries who have contributed to the data collection: Iceland: Arnar Gudjonson; Norway: Jan Folkvard Evensen, Odd Monge, Åsa Karlsdottir, Marianne Brydoy, Hanne Tondel, John Sigurd Lybeck, and Oddveig Rikardsen; Denmark: Kenneth Jensen; Sweden: Johan Wennerberg, Eva Brun, Magnus Niklasson, Hedda Haugen, Maciej Tytor, Måns Agrup, Jan Rzepecki, Anders Westerborn, Johan Reizenstein, Anders H€ogmo, Helena Sj€odin, Tomas Ekberg, Lena Cederblad, Magnus Wahlgren, and Karin S€oderstr€om; and Finland: Leif B€ack, Kauko Saarilahti, Jaakko Pulkkinen, Ilpo Kinnunen, Paula Lindholm, Reidar Grenman, Heikki Minn, Jussi Laranne, Tuija Wigren, Matti Pukkila, Leena Voutilainen, Petri Koivunen, and Merja Korpela. We would also like to acknowledge the Scandinavian Society for Head and Neck Oncology.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
ORCID
Lovisa Farnebo http://orcid.org/0000-0001-6722-7101 G€oran Laurell http://orcid.org/0000-0002-7760-246X Antti M€akitie http://orcid.org/0000-0002-0451-2404
References
[1] de Bree R. The real additional value of FDG-PET in detecting the occult primary tumour in patients with cervical lymph node metastases of unknown primary tumour. Eur Arch Otorhinolaryngol 2010;267:1653–5.
[2] Waltonen JD, Ozer E, Hall NC, Schuller DE, Agrawal A. Metastatic carcinoma of the neck of unknown primary origin: evolution and efficacy of the modern workup. Arch Otolaryngol Head Neck Surg 2009;135:1024–9.
[3] Dragan AD, Nixon IJ, Guerrero-Urbano MT, Oakley R, Jeannon JP, Simo R. Selective neck dissection as a therapeutic option in management of squamous cell carcinoma of unknown primary. Eur Arch Otorhinolaryngol 2014;271:1249–56.
[4] Jensen DH, Hedback N, Specht L, Hogdall E, Andersen E, Therkildsen MH, et al. Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival. PLoS One 2014;9: e110456.
[5] Yasui T, Morii E, Yamamoto Y, Yoshii T, Takenaka Y, Nakahara S, et al. Human papillomavirus and cystic node metas-tasis in oropharyngeal cancer and cancer of unknown primary origin. PLoS One 2014;9:e95364.
[6] Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous cell carcinoma from an unknown pri-mary. Cancer Treat Rev 2004;30:153–64.
[7] Issing WJ, Taleban B, Tauber S. Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol 2003;260:436–43.
[8] Chen AM, Marsano J, Perks J, Farwell G, Luu Q, Donald PJ, et al. Comparison of IMRT techniques in the radiotherapeutic management of head and neck cancer: is tomotherapy ‘‘better’’ than step-and-shoot IMRT? Technol Cancer Res Treat 2011; 10:171–7.
[9] Mistry RC, Qureshi SS, Talole SD, Deshmukh S. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary: outcomes and patterns of failure. Indian J Cancer 2008;45:54–8.
[10] Sun R, Tang X, Yang Y, Zhang C. (18)FDG-PET/CT for the detection of regional nodal metastasis in patients with head and neck cancer: a meta-analysis. Oral Oncol 2015;51:314–20. [11] Mohindra S, Bhattacharya A, Goshal S, Gupta B. Incremental
(?) role of positron emission tomography/computed tomography in clinically unknown primary patients with neck metastasis. Indian J Cancer 2014;51:142–4.
[12] Johansen J, Petersen H, Godballe C, Loft A, Grau C. FDG-PET/ CT for detection of the unknown primary head and neck tumor. Q J Nucl Med Mol Imaging 2011;55:500–8.
[13] Karni RJ, Rich JT, Sinha P, Haughey BH. Transoral laser micro-surgery: a new approach for unknown primaries of the head and neck. Laryngoscope 2011;121:1194–201.
[14] Koivunen P, Back L, Laranne J, Irjala H. Unknown primary: diagnostic issues in the biological endoscopy and positron emis-sion tomography scan era. Curr Opin Otolaryngol Head Neck Surg 2015;23:121–6.
[15] Nguyen NP, Vos P, Lee H, Borok TL, Karlsson U, Martinez T, et al. Impact of tumor board recommendations on treatment outcome for locally advanced head and neck cancer. Oncology 2008;75:186–91.
[16] Shoushtari A, Saylor D, Kerr KL, Sheng K, Thomas C, Jameson M, et al. Outcomes of patients with head-and-neck cancer of unknown primary origin treated with intensity-modulated radio-therapy. Int. J Radiat Oncol Biol Phys 2011;81:e83–91.
[17] Cuaron J, Rao S, Wolden S, Zelefsky M, Schupak K, Mychalczak B, et al. Patterns of failure in patients with head and neck carcinoma of unknown primary treated with radiation therapy. Head Neck 2016;38:E426–31.
[18] Chen AM, Farwell DG, Lau DH, Li BQ, Luu Q, Donald PJ. Radiation therapy in the management of head-and-neck cancer of unknown primary origin: how does the addition of concur-rent chemotherapy affect the therapeutic ratio? Int J Radiat Oncol Biol Phys 2011;81:346–52.
