DAHANCA.dk Danish Head and Neck Cancer Group

DAHANCA 16

Planned post-radiation neck dissection vs. salvage neck dissection in patients with N2/N3 squamous cell carcinoma of

the head and neck treated with primary curative intended radiotherapy

www.dahanca.dk

Version 1.0 (English version) 8 August 2005

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Coordinating Group DAHANCA sekretariat Principal Investigator: Department of Experimental Oncology Research fellow Anders Bilde, MD Århus Universitetshospital E-mail: bilde@rh.dk Nørrebrogade 44, bld. 5 DK-8000 Århus C Study Chairman: Tel. +45 8949 2619 Prof. Jens Overgaard, MD, DMSc Fax: +46 8619 7109 E-mail: jens@oncology.dk

Study coordinator, oncologi: Prof. Cai Grau, MD, DMSc E-mail: caigrau@dadlnet.dk

Study coordinator, surgery: Ass. prof. Christian Buchwald, MD, DMSc

E-mail: buchwald@rh.dk

Participating centres (Denmark) Finsencenteret, ONK 5073 Protocol responsible : H:S Rigshospitalet Overlæge, dr.med. Hanne Sand Hansen Blegdamsvej 9 E-mail: hsh@rh.dk DK-2100 København Ø Øre-Næse-Halskirurgisk Klinik Protocol responsible: H:S Rigshospitalet Overlæge, dr.med. Preben Homøe Blegdamsvej 9 E-mail: RH03259@rh.dk DK-2100 København Ø Onkologisk afd. Protocol responsible: Amtssygehuset i Herlev Overlæge Elo Andersen Herlev Ringvej E-mail: eland@herlevhosp.kbhamt.dk DK-2730 Herlev Øre-Næse-Hals Afdeling E Protocol responsible: Amtssygehuset i Gentofte Overlæge Henrik Møller Niels Andersens Vej 65 E-mail: HEMOL@gentoftehosp.kbhamt.dk DK-2900 Hellerup Onkologisk afd. R Protocol responsible Odense Universitetshospital Overlæge ph.d. Jørgen Johansen DK-5000 Odense C E-mail: j.johansen@dadlnet.dk Øre-Næse-Halskirurgisk Afdeling F Protocol responsible: Odense Universitetshospital Overlæge, ph.d. Christian Godballe DK-5000 Odense C E-mail: godballe@dadlnet.dk Onkologisk afd. D Protocol responsible: Århus Universitetshospital Overlæge Marie Overgaard Nørrebrogade 44, bld. 5 E-mail: marie@oncology.dk DK-8000 Århus C Øre-, næse- og halsafdeling H Protocol responsible: Århus Universitetshospital Overlæge, dr.med. Ulrik Pedersen Nørrebrogade 44, bld. 5 E-mail: ulrikpedersen@hotmail.dk DK-8000 Århus C Onkologisk afd. Protocol responsible: Aalborg Sygehus – afsnit Syd Overlæge Lisbeth J. Andersen DK-9100 Aalborg E-mail: aas.lja@nja.dk Øre-, næse- og halsafdeling H Protocol responsible: Aalborg Sygehus – afsnit Syd Overlæge Henrik Petersen DK-9100 Aalborg E-mail: U30313@aas.nja.dk

1. BACKGROUND AND INTRODUCTION........................................................................................................ 1 2. OBJECTIVE OF THE TRIAL ......................................................................................................................... 2 3. ENDPOINTS.................................................................................................................................................. 2

3.2.1 PRIMARY ENDPOINT ............................................................................................................................................... 2 3.2.2 SECONDARY ENDPOINTS ........................................................................................................................................ 2

4. TRIAL DESIGN.............................................................................................................................................. 3 4.1 REGISTRATION / INCLUSION ...................................................................................................................................... 3

5. BEFORE TREATMENT................................................................................................................................. 3 5.1 PATIENTS SELECTION CRITERIA................................................................................................................................. 3 5.3 CLINICAL EVALUATION AND LABORATORY TEST BEFORE TREATMENT ..................................................................... 4 5.4 INKLUSION, RANDOMISATION AND STRATIFICATION ................................................................................................. 4 5.5 QUALITY OF LIFE ...................................................................................................................................................... 4

6. THERAPEUTIC REGIMENS AND MODIFICATIONS................................................................................... 4 6.1 PRIMARY RADIOTHERAPY ......................................................................................................................................... 5 6.2 NIMORAZOL/NAXOGIN ............................................................................................................................................. 5 6.3 CT SCAN ................................................................................................................................................................... 5 6.4 NECK DISSECTION ..................................................................................................................................................... 5 6.5 SALVAGE NECK DISSECTION...................................................................................................................................... 5 6.6 TREATMENT WITHDRAWAL....................................................................................................................................... 5 6.7 AT THE END OF TREATMENT...................................................................................................................................... 6

7. CLINICAL EVALUATION AND FOLLOW-UP ............................................................................................... 6 7.1 ONE MONTH AFTER COMPLETION OF RADIOTHERAPY................................................................................................ 6 7.2 TWO MONTH AFTER COMPLETION OF RADIOTHERAPY............................................................................................... 6 7.3 FOLLOW-UP .............................................................................................................................................................. 6 7.4 AFTER RELAPSE / PROGRESSION ................................................................................................................................ 6

8 CRITERIA OF EVALUATION ......................................................................................................................... 7 8.1 REGIONAL CONTROL AND FAILURE ........................................................................................................................... 7 8.2 OVERALL SURVIVAL................................................................................................................................................. 7 8.3 DISEASE-SPECIFIC SURVIVAL .................................................................................................................................... 7 8.4 ACUTE SIDE EFFECTS OF RADIOTHERAPY .................................................................................................................. 7 8.5 LATE SIDE EFFECTS OF RADIOTHEARPY..................................................................................................................... 7 8.6 COMPLICATIONS FOLLOWING POST-RADIATION NECK DISSECTION ........................................................................... 7

9. STATISTICAL CONSIDERATIONS .............................................................................................................. 8 9.1 STATISTICAL DESIGN................................................................................................................................................. 8

9.1.1 Sample size ....................................................................................................................................................... 8 9.1.2 Randomization and stratifications.................................................................................................................... 8

9.2 ANALYSIS ................................................................................................................................................................. 8 9.2.2 Time to event analyses...................................................................................................................................... 8 9.2.3 Interim analyses ............................................................................................................................................... 9

11. ETHICAL CONSIDERATIONS.................................................................................................................... 9 12. REFERENCES ............................................................................................................................................ 9 13. APPENDIX I – NECK DISSECTION. ........................................................................................................ 11 14. APPENDIX II – ” DAHANCA 16 INCLUSION FORM”............................................................................... 12 15. APPENDIX III – ”DAHANCA 16 POST-RADIATION CT-SCAN AND TREATMENT”.............................. 13 16. APPENDIKS IV – PATIENTINFORMATION. .........................FEJL! BOGMÆRKE ER IKKE DEFINERET. 17. APPENDIX V – QUALITY OF LIFE. .......................................................................................................... 14 18. APPENDIKS VI - IKKE VIDENSKABELIG BESKRIVELSE AF PROJEKTET. ......FEJL! BOGMÆRKE ER IKKE DEFINERET.

1. Background and introduction There are approximately 700 cases per year in Denmark of laryngeal, pharyngeal and oral cancer, the majority being of squamous cell carcinoma origin. Squamous-cell carcinoma of the head and neck is predominantly a loco regional disease without distant metastases at the time of diagnosis (1). The primary treatment methods are surgery and radiotherapy.

In Denmark, there is a tradition of using primary radiotherapy to treat all laryngeal and pharyngeal carcinomas, and some tumours in the oral cavity. The treatment is coordinated by the Danish Head and Neck Cancer Study Group (DAHANCA). The treatment strategy of the DAHANCA protocols has been to select the best regimen from previous protocol changing one treatment parameter to see whether it will have an effect on treatment outcome. The DAHANCA 16 protocol is an example of this strategy adding post-radiation neck dissection in order to improve loco-regional control and disease-free survival. In the DAHANCA protocol 6 and 7 patients treated with primary radiotherapy alone were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (2). 1476 patients with glottic, supraglottic, larynx, pharynx, and oral cavity carcinomas were enrolled. The study concluded that the use of accelerated fractionation significantly improved the 5-year loco-regional tumour control (70 vs 60%, p=0·0005) as well as the disease-specific survival (73 vs 66 %, p=0.01) compared with conventional radiotherapy, but without improving the overall survival significantly. When the loco-regional endpoint was analysed for T-site and N-site failure individually, the whole benefit of acceleration was from improved T-site control (figure 1). In patients with N0-1 lymph node metastases however the loco-regional control (76 vs 66 % for six and five fractions) as well as the control of T-site (76 vs 66 % for six and five fractions) was improved significantly, whereas in patients with N2-3 there were no significantly improvement with six fractions per week on either the loco-regional control nor the control of T-site. In other words the accelerated fractioning did not have an effect on the control of N-site in patients with N2-3 even though failure at the T-site control was reduced.

It is generally agreed that patients with N1 lymph node metastases that completely regresses after radiotherapy can be observed with regard to neck recurrence whereas patients with N2-3 lymph node metastases who incompletely regresses after radiotherapy ought to undergo a planned neck dissection (3). However disagreement exist regarding a planned neck dissection following radiotherapy in patients with N2-N3 lymph node metastasis regardless of response to the radiotherapy. Proponents of planned neck dissection argue that even though the patients gains complete response to radiotherapy more than approximately 30 % will have positive nodes on histological examination following neck dissection (4-7). Proponents of observation argue the recurrence after complete

Figure 1: Effect of overall treatment time in T site and N site

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clinical response is very low (less than 8 %) even though a planned neck dissection has not been performed (8;9). Despite this disagreement it is in general agreed that combined treatment (planned neck dissection following radiotherapy) is advisable in patients with N2-3 lymph node metastases regardless of response to radiotherapy. The chances of cure (salvage surgery) are generally considered remote in case of a local recurrence because by the time it become apparent it has often become fixed to the surrounding structures including vital structures such as blood vessels (10-15). Methods for clinical assessment of residual neck disease after radiotherapy are still unreliable whether it is palpation, CT, MRI, ultrasound or FNA (16;17). The type of neck dissection that has been used following radiotherapy has differed between authors. The majority perform a radical neck dissection or a modified radical neck dissection (18-21). Some recommend a selective neck dissection covering level II-IV on the basis of the predictive pattern of lymph node metastases and do not recommend removal of lymph nodes in level I and V unless there are apparent lymph node metastasis (22;23). The interval between the completion of radiotherapy and the planned neck dissection has been 4 till 8 weeks (24-29). It is noticed that performing a neck dissection after 8 weeks of the completion of radiotherapy will be more difficult due to radiation-induced fibrosis (30). To perform a post-radiation neck-dissection are associated with an increased incidence of complications related to wound necrosis, skin separation or flap necrosis (31). Preoperative radiotherapy dose greater than 70 Gy are associated with a significant higher rate of complications the radiotherapy dose less than 70 Gy (32).

2. Objective of the trial The primary objective is to determine in an multicentre phase III randomised clinical trial whether planned post-radiation neck dissection can reduce the number of incurable regional failure in order to improve loco-regional control and disease-free survival in patients with N2/N3 squamous cell carcinoma of the head and neck treated with primary curative intended radiotherapy. The secondary objective is to determine the treatment morbidity following a post-radiation neck dissection. The tertiary objective is to determine whether post-radiation imaging can detect residual metastatic disease in order to select patients who will benefit from a post-radiation neck dissection

3. Endpoints

3.2.1 Primary endpoint Persistent regional control (N-site) following radiotherapy and/or surgery.

3.2.2 Secondary endpoints Local control (T-site). Loco-regional control. Disease-specific survival. Overall survival. CT-scan Post-radiation neck dissection complications. Quality of life (EORTC QLQ-C30 and HN35)

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4. Trial design Arm A (standard): Observation after completion of primary radiotherapy. Salvage neck dissection in case of recurrence. Arm B (experimental): Planned post-radiation neck dissection 6 weeks after completion of primary radiotherapy. It is mandatory to perform a CT scan 6 weeks after completion of radiotherapy in both arms. Other pre-operative imaging is optional. The decision for salvage neck dissection has to be based upon the clinical suspicion of recurrence and has to be confirmed with use of appropriate imaging modalities (CT, MRI, US, PET) and/or fine needle aspiration.

4.1 Registration / inclusion Patients who fulfil the inclusion criteria and are found to be eligible will be prospectively randomised into either Arm A or Arm B at the first head and neck conference.

Patients who fulfil the inclusion criteria will be asked to give written inform consent inform consent by the protocol responsible person at the head and neck centre.

Oral and written information will be given at the first consultation at the head and neck centre. Randomisation will occur before the radiation therapy. Radiation therapy should start within 3 weeks after randomisation.

5. Before treatment

5.1 Patients selection criteria a. Planned primary curative intended radiotherapy alone or combined chemo-radiotherapy

included patients randomised to either DAHANCA 9 ,DAHANCA 10 or ARTSCAN. b. Histological proven SCC in the oral cavity, oropharynx, hypopharynx or larynx, TNM

classification T1-T4, N2a, N2b, N2c contralateral or N3 unilateral, M0. c. Planned primary curative intended radiotherapy alone or combined chemo-radiotherapy d. No cervical lymph node metastases of squamous cell carcinoma from an unknown primary

(CUP) e. Radiotherapy must start within 3 weeks after randomisation

R A N D O M I Z E

Radiotherapy followed by observation. Salvage neck dissection in case of recurrence

Radiotherapy followed by planned neck dissection 6 weeks after completion of RT

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f. No prior treatment of the head and neck g. Patients must be sufficiently to undergo surgery h. No previous or current malignancies affecting the current treatment, evaluation or outcome i. Absence of any psychological, familial, sociological or geographical condition potentially

hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomisation in the trial

j. Age > 18 years k. WHO performance status 0-2 l. Written informed consent must be obtained and documented according to local and national

regulations

5.3 Clinical evaluation and laboratory test before treatment In order to be eligible for entry in this study, the following work-up procedures are mandatory:

a. Complete medical history including previous malignancies, assessment of tobacco use and alcohol use.

b. Clinical H&N examination of the upper aero-digestive tract and neck including an outline of the T-site and N-site.

c. Head and neck imaging with CT scanner or MRI of the T-site and N-site d. A chest x-ray to exclude any lung primary or metastasis. e. Ultrasound investigation of the neck is optional as well as tracheo-bronchie endoscopy. f. Laboratory test including Hgb and albumin.

5.4 Inklusion, randomisation and stratification For all eligible patients the ”DAHANCA 16 INCLUSION FORM” must be filled in. The checklist should be completed before the inclusion form is sent to the DAHANCA secretariat by fax for randomization: Fax +45 8619 7109.

If the patient fulfils the criteria for randomization the fax will return with a randomization number and the treatment (either arm A or B) to be given. Included patients will be stratified by:

a. Institution b. The localisation of the tumor (cavum oris, pharynx og larynx) c. T-classification d. N-classification

The DAHANCA “ON STUDY” form has to be filled out as well as soon as possible through the Internet.

5.5 Quality of life At time of randomisation EORTC QLQ-C30, QLQ H&N35 will be given to the patient. These forms will be used as a baseline (for further information, see appendix V).

6. Therapeutic regimens and modifications All included patients will be seen on a regularly basis during treatment and developments has to be reported on the “DAHANCA 2000 CONTROL UNDER TREATMENT” form.

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6.1 Primary radiotherapy All patients are going to treated with primary curative intended radiotherapy. The selection and delineation of clinical target volume (CTG) follows the guidelines of DAHANCA. The guidelines can be downloaded at www.dahanca.dk.

6.2 Nimorazol/Naxogin All patients will received the hypoxic radiosensitiser nimorazole according to DAHANCA guidelines.

6.3 CT scan A mandatory CT scan is to be performed 6 weeks after completion of primary radiotherapy.

The CT scan is evaluated for both arms according to local guidelines in order to determine response to the radiotherapy.

For patients randomised to post-radiation neck dissection (arm B) the CT scan has to be performed immediately prior to the operation. The result of the scan has to be reported on the ”DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form.

6.4 Neck dissection For patients randomised to post-radiation neck dissection (arm B) the neck dissection has to be performed within 6 weeks after completion of primary radiotherapy. The neck dissection has to be performed regardless of the response to the radiotherapy. For this reason the type of neck dissection and levels to be treated has to be decided prior to the radiotherapy.

The neck dissection is only performed in case the patient is either without recurrence at the T-site or if it is possible to treat the recurrence at the T-site. In other words a neck dissection is not performed in case of an incurable T-site following primary radiotherapy. For this reason an inspection / endoscopy has to be performed prior to the operation in order to determine whether the patient should undergo an operation. If in doubt a biopsy can be taken for frozen-section analysis.

For a more detail description of the different types of neck dissection please refer to appendix 1. A selective neck dissection covering level II to IV should be performed in most cases of a neck metastasis in level II and III. The neck dissection ought not to include level I or level V on regular basis, but in case of a neck metastasis located lateral in level IIb or profound in level IV the neck dissection should include level V, and if the primary tumour is located within the oral cavity level I ought to be included. If a radical neck operation cannot be achieved using a selective neck dissection a modified radical or a radical neck dissection can be performed instead.

The type of neck dissection used and the result of the histopatological examination of the neck specimen have to be reported on the “DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form.

6.5 Salvage neck dissection The decision for salvage neck dissection for patients randomised to observation after radiotherapy has to be based upon the clinical suspicion of recurrence and has to be confirmed with use of appropriate imaging modalities (CT, MRI, US or PET) and/or fine needle aspiration.

6.6 Treatment withdrawal Protocol treatment will be discontinued in case of:

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1. The surgeon judges the patient inoperable after the completion of primary radiotherapy. 2. Disease progression during treatment 3. Patient refusal 4. Any other event clearly not in the interest of the patient

Treatment withdrawal has to be reported on on the “DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form.

6.7 At the end of treatment At the end of treatment 2 months after primary radiotherapy the ”DAHANCA 2002 PRIMARY TREATMENT” form and the “DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form has to be filled out and sent to the DAHANCA secretariat.

7. Clinical evaluation and follow-up

7.1 One month after completion of radiotherapy Patients will be evaluated 2 till 4 weeks after completion of radiotherapy in order to access acute toxicity to radiotherapy using the Common Toxicity Criteria (CTC, version 2-0). The ”DAHANCA 2002 ON TREATMENT ASSESSMENT” form and quality of life form (EORTC QLQ-C30, QLQ H&N35) has to be filled out.

7.2 Two month after completion of radiotherapy Patients will be evaluated two month after completion of radiotherapy in order to access toxicity to radiotherapy, loco-regional control as well as post-irradiation neck dissection complications for patients randomized to planned post-irradiation neck dissection. The ”DAHANCA 2002 ON TREATMENT ASSESSMENT” form and quality of life form (EORTC QLQ-C30, QLQ H&N35) has to be filled out.

7.3 Follow-up All patients are followed for at least 5 years after completion of radiothearpy. The ”DAHANCA 2002 FOLLOW-UP” form are used. The patients will be evaluated in the first year 5, 8 and 12 month after completion of radiotherapy. The second year at least every 4 months. The third to fifth year at least every 6 months. If any side effects arises since last follow-up the treatment of it has to be registered.

Quality of life (EORTC QLQ-C30 and HN35) has to be filled out at follow-up 5, 8 and 12 months after completion of radiotherapy. The clinical suspicion of recurrence or persistent carcinoma has to be confirmed with use of appropriate imaging modalities (CT, MRI, US, PET) and/or fine needle aspiration. Distant metastases are treated according to local guidelines.

7.4 After relapse / progression I case of relapse or progression patients are treated according to local guidelines.

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8 Criteria of evaluation

8.1 Regional control and failure Regional control will be measured from the date of randomization to the date of first occurrence of regional failure. Regional failure is defined as incurable recurrence at the N-site. Documentaion of incurable recurrence has to be done with the use of CT, MRI or PET scan. Documentation of the histology ought to be done as well.

Any of the following events will be regarded as regional failure:

a. Regional progression or incurable recurrence, which can not be treated at any time. b. A none-radical neck dissection will be regarded as regional failure from the date of the

planned neck dissection in case residual cancer is proven histologically.

Successful treatment of recurrence at the N-site for both arms will not be considered as regional failure.

8.2 Overall Survival Overall survival will be measured from the date of randomization to the date of death whatever the cause of death.

8.3 Disease-specific survival Disease-specific survival will be measured from the date of randomization to the date of death if the cause of death is loco-regional disease or metastasis from the primary cancer. Patients dieing of other causes will be censored in the analysis.

8.4 Acute side effects of radiotherapy Acute side effects of radiotherapy has to be registered using the ”DAHANCA 2002 ON TREATMENT ASSESSMENT” form. These side effects will be registered on a daily basis during treatment and 2 months after completion of radiotherapy. Unwanted side effects 2 months after will be regarded as late side effects.

8.5 Late side effects of radiothearpy Late side effects of radiotherapy will be registered on the ”DAHANCA 2002 FOLLOW-UP” form.

8.6 Complications following post-radiation neck dissection The type of neck dissection and the levels and structures included has to be registered on the ” “DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form.

Complications following post-radiation neck dissection has to be registered on the “DAHANCA 16 POST-RADIATION CT SCAN AND TREATMENT” form.

Late post-radiation complication to neck dissection has to be registered on the ”DAHANCA 2002 FOLLOW-UP” form.

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9. Statistical considerations

9.1 Statistical design

9.1.1 Sample size The primary objective is to determine in an open randomised trial whether planned post-radiation neck dissection, compared to salvage neck dissection, has an effect on loco-regional control and disease specific survival in patients with N2/N3 squamous cell carcinoma of the head and neck treated with primary radiotherapy. The five year recurrence rate at the N-site for N2/N3 for patients treated with accelerated radiotherapy is approximately 50 % of which half of the patients at the same will have an incurable recurrence at the T-site. Thus, approximately 25 % of the patients are expected to have an isolated recurrence at the N-site. The aim of the DAHANCA 16 trial is to reduce this percentage by 10 procent to approximately 15 %. With a statistical power of 80 % and a level of significance at 5 % it is calculated that this will require approximately 60 events. Since isolated recurrence at the N-site occurs often immediately after completion of radiotherapy, it is expected that more that 80 % of the events will take place during the trial. Thus, a total number of 300 patients are calculated to be included in the trial (150 patients in each arm). With more than 100 expected patients per year the trial will close after three years. A final analysis will take place after the 60 events have been reached.

9.1.2 Randomization and stratifications Patients will be centrally randomized at the DAHANCA sekretariat. The patients to be included will be stratified according to the stratifications criteria section 5.4.

9.2 Analysis

9.2.2 Time to event analyses All time to event endpoint will be estimated using the Kaplan-Meier method and compaired using the Logrank test.

a. Loco-regional control will be measured from the date of randomization to the date of the

first documented occurrence of loco-regional failure. Patients that are alive and without sign of loco-regional occurrence/progression at the time of analyses, and patients that are dieing or develops metastasis without evidence of loco-regional occurrence/progression will be censored on the date for the last follow-up, death or documentation of metastasis.

b. Local control (T-site) will be measured form the date of randomization to the date of the first documented occurrence of local failure.

c. Regional kontrol (N-site) will be measured from the date of randomization to the date of the first documented occurrence of incurable regional failure. Successful treatment of recurrence at the N-site for both arms will not be considered as regional failure.

d. Overall survival will be measured from the date of randomization to the date of death whatever the cause of death.

e. Disease-specific survival will be measured from the date of randomization to the date of death if the cause of death is loco-regional disease or metastasis from the primary cancer. Patients dieing of other causes will be censored from the date of last follow-up or death. in the analysis

f. Acute and late side effects of radiotherapy and complications following post-radiation neck dissection will be registered as written above and compared using the Chi square test.

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9.2.3 Interim analyses The quality of the treatment, the acute and late side effects and complications following post-radiation neck dissection will be reviewed within the group without any formal statistical analysis. It will be presented at groups meetings and will be discussed with the investigators. 10. Translationel research A translational research program will be initiated in the framework of this clinical trial. Blod as well as tissue samples will be collected for later analysis of factors which could be of importance for recurrence.

11. Ethical considerations The trial is a multicentre phase III randomised trial which is conducted according to the Declaration of Helsinki. The protocol will be approved by the Local, Regional or National Ethics Committees. Participating patients will receive written as well as oral information concerning the trial.

12. References

1. Overgaard J, Hansen HS, Jorgensen K, Hjelm HM. Primary radiotherapy of larynx and pharynx carcinoma--an analysis of some factors influencing local control and survival. Int.J.Radiat.Oncol.Biol.Phys. 1986;12(4):515-21.

2. Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362(9388):933-40.

3. Mendenhall WM, Villaret DB, Amdur RJ, Hinerman RW, Mancuso AA. Planned neck dissection after definitive radiotherapy for squamous cell carcinoma of the head and neck. Head Neck 2002;24(11):1012-8.

4. Wang SJ, Wang MB, Yip H, Calcaterra TC. Combined radiotherapy with planned neck dissection for small head and neck cancers with advanced cervical metastases. Laryngoscope 2000;110(11):1794-7.

5. Lavertu P, Adelstein DJ, Saxton JP, Secic M, Wanamaker JR, Eliachar I et al. Management of the neck in a randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer. Head Neck 1997;19(7):559-66.

6. Roy S, Tibesar RJ, Daly K, Pambucian S, Lee HK, Gapany M et al. Role of planned neck dissection for advanced metastatic disease in tongue base or tonsil squamous cell carcinoma treated with radiotherapy. Head Neck 2002;24(5):474-81.

7. Lee HJ, Zelefsky MJ, Kraus DH, Pfister DG, Strong EW, Raben A et al. Long-term regional control after radiation therapy and neck dissection for base of tongue carcinoma. Int.J.Radiat.Oncol.Biol.Phys. 1997;38(5):995-1000.

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8. Peters LJ, Weber RS, Morrison WH, Byers RM, Garden AS, Goepfert H. Neck surgery in patients with primary oropharyngeal cancer treated by radiotherapy. Head Neck 1996;18(6):552-9.

9. Johnson CR, Silverman LN, Clay LB, Schmidt-Ullrich R. Radiotherapeutic management of bulky cervical lymphadenopathy in squamous cell carcinoma of the head and neck: is postradiotherapy neck dissection necessary? Radiat.Oncol.Investig. 1998;6(1):52-7.

10. Boyd TS, Harari PM, Tannehill SP, Voytovich MC, Hartig GK, Ford CN et al. Planned postradiotherapy neck dissection in patients with advanced head and neck cancer. Head Neck 1998;20(2):132-7.

11. Mabanta SR, Mendenhall WM, Stringer SP, Cassisi NJ. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck 1999;21(7):591-4.

12. Narayan K, Crane CH, Kleid S, Hughes PG, Peters LJ. Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all? Head Neck 1999;21(7):606-13.

13. Doweck I, Robbins KT, Mendenhall WM, Hinerman RW, Morris C, Amdur R. Neck level-specific nodal metastases in oropharyngeal cancer: is there a role for selective neck dissection after definitive radiation therapy? Head Neck 2003;25(11):960-7.

14. Robbins KT, Wong FS, Kumar P, Hartsell WF, Vieira F, Mullins B et al. Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer. Arch.Otolaryngol.Head Neck Surg. 1999;125(6):670-5.

15. Genden EM, Ferlito A, Shaha AR, Talmi YP, Robbins KT, Rhys-Evans PH et al. Complications of neck dissection. Acta Otolaryngol. 2003;123(7):795-801.

16. Davidson BJ, Newkirk KA, Harter KW, Picken CA, Cullen KJ, Sessions RB. Complications from planned, posttreatment neck dissections. Arch.Otolaryngol.Head Neck Surg. 1999;125(4):401-5.

17. Robbins KT, Clayman G, Levine PA, Medina J, Sessions R, Shaha A et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery. Arch.Otolaryngol.Head Neck Surg. 2002;128(7):751-8.

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13. Appendix I – Neck dissection. The Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) has developed a standardised classification system of the region lymph nodes of the neck into six levels I-VI with additional sublevels IA, IB, IIA, IIB,VA and VB. The standard surgical procedures will be a selective neck dissection (SND) covering level II-IV. Selective neck dissection refers to a cervical lymphadenectomy in which there is preservation of 1 or more of the lymph node groups that are routinely removed in the radical neck dissection Radical neck dissection (RND) refers to the removal of all ipsilateral cervical lymph node groups extending from the inferior border of the mandible to the clavicle, from the lateral border of the sternohyoid muscle, hyoid bone, and contralateral anterior belly of the digastric muscle medially, to the anterior border of the trapezius muscle. Included are all lymph nodes from levels I through V. The SAN, internal jugular vein, and SCM are also removed. Modified radical neck dissection (MRND) refers to the excision of all lymph nodes routinely removed by the radical neck dissection with preservation of 1 or more nonlymphatic structures (ie, the SAN, internal jugular vein, and SCM). Whenever possible a modified radical neck dissection will be favoured. In case of larger neck node metastasis or lymph nodes metastasis with extranodal spread the use of an extended neck dissection (END) may be necessary. Extended neck dissection refers to the removal of 1 or more additional lymph node groups or nonlymphatic structures, or both, not encompassed by the radical neck dissection.

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14. Appendix II – ” DAHANCA 16 INCLUSION FORM” DAHANCA-16 Inclusion Form Randomization and registration (this form does not replace On Study Form) include Checkliste for inklusionskriterierne Histological proven squamous cell carcinoma (SCC) in the cavum oris, larynx, oropharynx, hypopharynx or larynx _ No _ Yes SCC i rhinopharynx eller SCC from an unknown primary _ Yes _ No TNM classification T1-T4, N2a, N2b, N2c contralateral eller N3 unilaterat _ No _ Yes TNM classification N2c bilateral eller N3 bilateral _ Yes _ No Distant metastasis _ Yes _ No Candidate for primary curative intended radiotherapy _ No _ Yes Sufficient to undergo surgery _ No _ Yes No prior treatment of the head and neck _ Yes _ No Radiotherapy must start within 3 weeks after randomisation _ No _ Yes CT-scan performed 6 weeks after completion of radiotherapy _ No _ Yes No previos or current malignancies affectin the current treatment, evaluation or outcome _ Yes _ No Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance _ Yes _ No Age > 18 years _ No _ Yes WHO performance status 0-2 _ No _ Yes Written informed consent according to local and national regulations _No _ Yes Stratification parameters (to be filled in before randomization and registration) Institution 1:Finsen; 2:Herlev; 3:Odense; 4:Århus; 5:Ålborg; 7:Oslo ______ T-site Cavum oris

Pharynx Larynx T-classification T1 2 N-classification N2a 3 (UICC TNM 1997) T2 5 N2b 4 T3 6 N2c contralateral 5 T4 7 N2c bilateral 7 N3 6 Signed written Yes consent No Date (dd-mm-yy) ______-______-______ Approved by Signature ____________________________ In block letters__________________________ ……………………………To be faxed to the DAHANCA sekretariat + 45 8619 7109……………………………………………………………. Randomisation (to be filled in by the DAHANCA secretariat and returned with a randomization number) Randomization date ______-______-______ Randomization group Post-radiation neck dissection 1 Observation 2 Randomization number ____-____-____-____-____-____

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15. Appendix III – ”DAHANCA 16 POST-RADIATION CT-SCAN AND TREATMENT”. DAHANCA-16 Post-radiatorisk CT-scan and Treatment The form is only to be used for patients randomized to post-radiation neck dissection. Resultat of the CT-scan after completion of radiotherapy (6weeks) Recurrence at the N-site Yes No Anatomical location Ipsilateral Contralateral I I II II III III IV IV V V VI VI Reason for omitting the neck dissection 1: Judge to be inoperable at the T-site Yes No 2: Judge to be inoperable at the N-site Yes No Neckdissection Type of neckdissection Unilateral neck dissection Bilateral neck dissection Included levels Ipsilateral Contralateral I I II II III III IV IV V V VI VI Modification Ipsilateral Contralateral SCM included IJV included SAN included Extended neck dissection Ipsilateral Contralateral Structures included: ____________________________________________________________________________________________________________ Complication following post-radiation neck dissection 1: Fistula Yes No 2: Bleeding demanding transfusion Yes No 3: Reoperation due to bleeding Yes No 4: Infection Yes No 5: Necroses Yes No 6: Paralyse of the nerves Yes No Nerves included: __________________________________________________________________________________________________________ Result of the histopatological examination of the neck specimen _____ Result of the histopatological examination of the primary tumor _____ 1: No specimen 3: Tumour visible – radical operation 2: Tumour not visible 4: Tumour visible – uncertain radical 5. Tumour visible – non-radical operation Date (dd-mm-yy) ______-______-______ Approved by Signature ____________________________ Block letters___________________________

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17. Appendix V – Quality of life. Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. This is composed multi-item and single scales. These include five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QOL scale and six single items (dyspnoa, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single items meet the standards for reliability. While EORTC Quality of Life Questionnaire (QLQ-C30) lacks some dimensions that pertain to the QoL issues in certain cancers it is often combined with a tumour-specific module – the EORTC QLQ-H&N35. The EORTC QLQ-H&N35 was designed to assess QoL in head and neck cancer patients. It contains seven symptom scales (pain, swallowing, senses (taste/smell), speech, social eating, social contact, sexuality), six symptom items (teeth problems, problems opening mouth (trismus), dry mouth, sticky saliva, cough, feeling ill) and five additional items concerning the use of pain killers, nutritional symptoms and a feeding tube, weight loss and weight gain. The patients has to fill in the EORTC's QLQ-C30 og QLQ-H&N35 prior to treatment (baseline) and after completion of the radiotherapy and at follow-up 5, 8 and 12 months after completion of radiotherapy.

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