Quality of Life After primary TORS vs IMRT The QoLATI ... 34.pdf · Katalin Kiss, MD3 Claus Jensen, MD4 Affiliations, Rigshospitalet 1. Department of Otorhinolaryngology, Head and

Etisk komité nr.: 63669 Tillægsprotokol vers. 3.0 Revideret 28.09.2018

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Quality of Life After primary TORS vs IMRT

"The QoLATI study”

for patients with early-stage oropharyngeal

squamous cell carcinoma: A Randomized

National Trial

Registered DAHANCA 34 protocol

Sponsor-Investigator*

Christian von Buchwald, Professor, DMSc.1

Email: [email protected]

*Takes responsibility for the initiation, management and/or financing of a clinical study. The obligations of sponsor-

investigator include both those of a sponsor and those of an investigator.

Principal Investigator**/***, Department of Otorhinolaryngology, Head and Neck Surgery

and Audiology, Rigshospitalet

Niclas Rubek, MD1


**Principal investigator is the responsible leader of the investigator team

Investigator***, Oncology Department, Rigshospitalet and Herlev Hospital

Jeppe Friborg, MD, PhD2


***Investigator role is the responsible person for conducting the protocol at each department.


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Trial coordinators, Rigshospitalet

Hani Ibrahim Channir, MD, PhD1

(H.I.C has contributed substantially to the conception of the protocol)

Anne Kathrine Østergaard Madsen1

Co-investigators, Rigshospitalet

Jesper Filtenborg Tvedskov, MD, PhD1

Birgitte Wittenborg Charabi, MD1

Irene Wessel, MD, PhD1

Susanne Irene Scott, MD1

Ivan Vogelius, Professor, Dr.med.2

Anne Fog Lomholt, MD, PhD1

Katalin Kiss, MD3

Claus Jensen, MD4

Affiliations, Rigshospitalet

1. Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet

2. Department of Oncology, Rigshospitalet

3. Department of Pathology, Rigshospitalet

4. Department of Radiology, Rigshospitalet

Investigator***, Department of Oncology, Herlev University Hospital

Jens Bentzen, MD


Investigator***, Department of Oncology, Næstved Sygehus

Mohammad Farhadi, MD



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Investigator***, Department of Otorhinolaryngology - Head & Neck Surgery, Odense

University Hospital

Christian Godballe, Professor, MD, PhD


Investigator***, Department of Oncology, Odense University Hospital

Jørgen Johansen, MD, PhD




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Co-Investigators, Odense University Hospital

Bahareh Philipsen, MD1

Peter Darling, MD1

Stine Rosenkilde Larsen, MD2

Affiliations, Odense University Hospital

1) Department of Otorhinolaryngology - Head & Neck Surgery

2) Department of Pathology

Investigator***, Department of Otorhinolaryngology - Head & Neck Surgery, Aarhus

University Hospital

Thomas Kjærgaard, MD, PhD


Investigator***, Department of Oncology, Aarhus University Hospital

Jesper Eriksen, MD, PhD



Co-Investigators, Aarhus University Hospital

Pernille Lassen, MD, PhD2

Karin Aksglæde1

Dalia Larsen, MD1

Arunas Pikelis, MD1

Kenneth Jensen, MD, PhD2

Benedicte Parm Ulhøi3

Edith Nielsen, MD4

Affiliations, Aarhus University Hospital

1) Department of Otorhinolaryngology - Head & Neck Surgery

2) Department of Oncology

3) Department of Pathology

4) Department of Radiology


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Responsible for radiotherapy Quality Assurance

Christian Rønn Hansen, Medical Physicist, Department of Oncology, Odense University Hospital

DAHANCA secretariat

DAHANCA secretariat

Department of Experimental Clinical Oncology

Aarhus University Hospital

Noerrebrogade 44, Bldg. 5

DK-8000 Aarhus C, Denmark

Phone: +45 7846 2620

Fax.: +45 8619710


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Introduction

Oropharyngeal cancer and Human Papillomavirus

Oropharyngeal squamous cell carcinoma (OPSCC) is now the most frequently diagnosed head and

neck cancer with about 450 new cases a year in Denmark. Epidemiological studies from Denmark

have shown that there has been a continuously rising incidence rates from 2000-2014, which is

mainly due to the increase of Human Papillomavirus (HPV) induced OPSCC [1–3]. HPV-positive

OPSCC represents a new group compared to the tobacco and alcohol associated tumours. The

patients tend to be younger, healthier, much more likely to be employed at the time of diagnosis and

have a significantly higher survival rate (especially for the combined p16 and HPV DNA positive

subgroup), with a 5-year survival rate of over 70% [4,5]. It is therefore increasingly important to

investigate not only the functional outcomes, but also the time it takes before patients can return to

work. HPV-positive oropharyngeal cancers have a strong predilection for the palatine tonsils or the

base of tongue. The traditional primary treatment modality in Denmark is Intensity Modulated

Radiation Therapy (IMRT), and in advanced stages this is combined with chemotherapy. The

treatment is very effective, especially in cancers with a high expression of the surface protein p16

[5–8]. However, the combined IMRT and chemotherapy treatment is associated to a wide range of

short and long-term side effects [9–11]. There is therefore a growing interest in minimally invasive

surgical treatment of HPV-positive OPSCC [12].

Prognostic factors for oropharyngeal cancer

According to the new TNM Classification of Malignant Tumours described below, essential tumour

related prognostic factors for oropharyngeal cancer include HPV status (including p16), tumour and

nodal stage. Essential host related prognostic factors include smoking (especially during

radiotherapy) and performance status.

A recent study which included all patients diagnosed with OPSCC (n = 1,542) between 2000-2014

in Eastern Denmark performed an individual risk-profile for overall survival (OS), time to

progression (TTP), and survival after progression (SAP) in patients with HPV-positive and HPV-

negative OPSCC [5]. Univariate analysis of factors influencing overall survival showed that HPV-

negative and p16 negative tumours together with pack years of smoking, treatment, tumour

location, and T, N, and M classification were significantly associated to a poorer OS. However,


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subsequent multivariate Cox regression model showed that the HPV-positive/ p16-positive status

was an independent predictor for OS, even when adjusted for T-stage, N-stage, treatment, smoking

history, age, and performance status.

In the current protocol, treatment will be stratified based on p16 status. p16 positivity or

overexpression is defined as more than 70% of the cancer cells (in our files we will also note if

>75%). HPV-DNA analysis will also be performed and included in data analyses including

survival and recurrence outcomes.

TNM Classification of Malignant Tumours

In the current protocol we will use the TNM Classification of Malignant Tumours, 8th edition

published in 2016 by the Union For International Cancer Control (UICC), Tables 1 and 2 in

addendum [13]. The biggest difference compared to the 7th edition, is that p16-positive OPSCC

(base of tongue and palatine tonsils only) has its own classification system different from p16-

negative cancers of the oropharynx (or oropharyngeal cancers without p16-immunohistochemistry

performed). In the new pathological tumour and nodal classification (pT and pN), pathologic T-

stage (pT-categories) corresponds to the cT categories (Table 1). The definition of pN stages in

p16-positive and p16-negative patient groups are defined in Table 2.

In the following study protocol we define the following subgroups:

• Patients with p16* positive primary tumour with a maximum size of 4cm, and either no

regional lymph node metastasis or solitary ipsilateral metastasis measuring ≤ 3cm.

*We have chosen a conservative approach to the new TNM p16+ N-classification since we do

not include p16+ patients with lymph node metastasis bigger than 3cm in greatest diameter.

Larger N-site volume increases the risk of ECE as well as intraoperative complications. We also

do not include patients with more than one lymph node metastasis, regardless of size, or patients

with contralateral lymph node metastasis.


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• Patients with p16 negative primary tumour with a maximum size of 4 cm and either no

regional lymph node metastasis or solitary ipsilateral metastasis measuring ≤ 3cm

Transoral robotic surgery (TORS)

Since 2009, TORS has enabled surgeons to perform minimally invasive surgery as an alternative to

the traditional oncological treatment. TORS is increasingly used in OPSCC resections. Its use of a

three-dimensional endoscope and hinged instruments improves surgical accessibility to areas that

was not previously accessible for en bloc resections in the oro- and hypopharyngeal cavity [14].

TORS has been shown to be more precise and tissue sparing hereby reducing treatment-related

morbidity compared to traditional radical surgery [15,16].

Rigshospitalet has performed more than 210 TORS procedures and is currently the leading TORS

center in Scandinavia. At Aarhus University Hospital, TORS was implemented in 2015 and has

currently performed more than 40 procedures. In many countries, treatment of early-stage OPSCC

with primary TORS is considered equal to primary radiotherapy in terms of survival. Patients are

therefore able to choose freely between the two treatment modalities. In a recent multicentre study

across 11 treatment centres 364 patients with OPSCC were treated with TORS with or without (±)

radiochemotherapy (adjuvant therapy). The study showed excellent results with a two-year disease

free survival of 94.5% (95% CI; 90.6-96.8%) and overall survival of 91% (95% CI; 86.5-94.0%)

[17]. Primary TORS±adjuvant therapy is an effective treatment option for patients with p16-

positive OPSCC, which further supports the fact that HPV-positive and HPV-negative OPSCC

represent two clinically separate disease entities [18].

The morbidity and mortality associated with primary TORS followed by IMRT has so far not been

thoroughly investigated. It is possible that the combination of the three treatment modalities may

lead to increased morbidity. There is a lack of randomised trials comparing primary radiotherapy

with TORS. Current data is mostly derived from retrospective studies with selection bias and

varying methods as well as inclusion criteria. Primary oncological treatment for OPSCC is the first

line choice in many countries, however TORS is increasingly being offered as an alternative,

especially in early-stages. Several small retrospective studies have shown promising results when

comparing the two treatment modalities in favour of TORS with regards to treatment related pain,

dysphagia, speech and quality of life (QoL) with similar oncological outcomes [19–21].


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Margin Control

In primary surgery there is risk of not achieving radical tumour resection, which if possible requires

either re-resection or postoperative IMRT±concurrent chemotherapy. Non-radical resection can

occur for several reasons including: underestimated tumour size, unexpected location or proximity

to unresectable structures such as main vessels or functionally important nerves. Another important

factor is the surgeon’s level of experience i.e. the ability to achieve adequate tumour resection with

a minimal amount of collateral damage.

According to the Royal College of Pathologists, best practice for resection margins (pharynx) are

classified as follows: < 1mm involved margin, 1-5mm close margin and > 5mm free margin

(Dataset for histopathology reporting of mucosal malignancies of the pharynx, 2013). In 2012,

Weinstein et al published a study of 30 patients with T1-3 OPSCC, who were treated with primary

TORS and neck dissection without adjuvant therapy [22]. They considered resection margins of

more than 2 mm as radical resection and found only one recurrence at the tumour site (T-site)

during the observation period. This also includes a supplementary free margin achieved either at the

primary or a secondary surgical procedure. One patient had a re-resection to obtain free resection

margins. Free resection margins of 2 mm or more have been shown to be adequate in achieving

local control in earlier reports [23]. Recently, a study from Rigshospitalet was published comprising

30 consecutive patients with early stage OPSCC who had undergone primary TORS treatment using

a minimum of 2 mm cut off for a free margin [24]. Twenty-nine patients had negative margins on

T-site after primary resection and only one patient had a close margin of 1 mm. However, 13

patients were referred to adjuvant therapy after TORS because of pN-site upstaging, three of which

had triple-modality treatment with TORS and concurrent radiochemotherapy.

In the current protocol, we define a margin as free if it is a minimum of 2 mm wide or if a

secondary supplementary margin is free.

Lymph node involvement and extracapsular extension

It is widely accepted that extracapsular extension (ECE) increases the risk of N-site failure but there

is currently no high-level evidence to clarify the benefit of postoperative adjuvant therapy for

patients with HPV/p16-positive OPSCC with pN2a/pN2b status (TNM, 7th edition) or ECE in nodal

metastases [25]. We have not found any studies that evaluate the effect of adjuvant therapy on


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regional control in the subgroup of patients with positive HPV status. The national guidelines from

the Danish Head and Neck Cancer Group (DAHANCA) recommend that adjuvant therapy is

indicated if the risk of N-site recurrence is 10% or more.

One retrospective study included a total of 2,454 patients (majority being non-hispanic white men)

with HPV-positive (by in situ hybridization or p16 overexpression) from the National Cancer Data

Base in the United States (represents 70% of all cancer cases in the US) showed that the presence of

ECE and other traditional high-risk features has a limited prognostic impact on overall survival in

HPV-positive oropharyngeal cancer [26]. Other retrospective studies which only included patients

with p16-positive OPSCC, have indicated that the impact of ECE in nodal metastases is limited and

that the presence of only gross ECE (soft tissue involvement) may justify the addition of

chemotherapy [27–29]. It is however important to underline, that these retrospective studies are not

powered to make any conclusions. In a recent review it was speculated, that the lack of prognostic

value of ECE in patients who have been treated with postoperative radiochemotherapy vs. radiation

therapy alone may reflect the fact that HPV-positive OPSCC is highly radiosensitive, such that

additional chemotherapy has minimal benefit [30]. A change of current guidelines should not be

implemented without prospective data that aims to clarify the clinical significance of ECE and the

need for radiochemotherapy. Currently, there are two ongoing randomized trials (ECOG 3311 and

ADEPT study) which aim to assess the intensity of adjuvant therapy required in patients with p16

positive oropharyngeal cancer with presence of ECE in their positive lymph nodes.

ECE is not included in the grading of p16 positive OPSCC according to the UICC TNM

classification 8th edition. In the current protocol, the presence of ECE in nodal metastases is

defined as macro- or microscopic extension of tumour breaching the lymph node capsule.

Neck Dissection

Several studies have examined the incidence of lymph node spread to the neck in OPSCC. As many

as 20-30% of the patients are found to have lymph node involvement despite clinically negative

(cN0) disease and therefore it is recommended to perform either ipsilateral or bilateral neck

dissections of level II-IV even when no lymphatic spread can be detected pre-operatively [31,32].


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In the current protocol, patients with a primary palatine tonsil tumour who are included in

the experimental arm (TORS), will undergo ipsilateral neck dissection of lymph node levels

II-IV. Patients with a primary base of tongue cancer or with significant involvement of tongue

base or the soft palate defined as above 1 cm, will be offered a bilateral neck dissection of

levels II-IV.

Stratification of treatment based on neck status in experimental arm

Eligible patients in the experimental arm will be stratified to treatment based on their clinical neck

status i.e. cN+ or cN0 according to the DAHANCA guidelines.

Patients with clinically positive neck (cN+) will be offered a staging neck prior to TORS. Based on

final pathology of the neck specimen, patients will either be referred for definitive IMRT±

concurrent chemotherapy (extracapsular spread or more than two lymph node metastases) or they

will undergo TORS (no extracapsular spread and maximally two lymph node metastases). A flow

diagram is shown in study design figure 1.

Patients with cN0 will undergo neck dissection before or concurrently with TORS. A staging neck

is not necessary as the risk of upstaging after histological examination is considered low.

To ensure minimal delay between neck dissection and TORS, the procedures will be performed

within 8 calendar days apart if not performed concurrently as a same day procedure.

Lymph node yield

A review of the literature showed that the lowest mean nodal yield was 26.4 for selective neck

dissection level II-IV [33]. In a recent study performed by Rigshospitalet, the median lymph node

yield per selective neck dissection (levels II-IV on each side) was 23 lymph nodes [33].

The new UICC, TNM classification, 8th edition requires a minimum nodal yield of 10 lymph

nodes per selective neck dissection on each side which is also the gold standard in the current

study.


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Morbidity after primary TORS and radiotherapy

Current literature suggests that patients with early-stage HPV/p16 positive OPSCC may be offered

surgery alone while patients with advanced stages should be offered intensified treatment with

surgery (if eligible) and adjuvant IMRT±concurrent chemotherapy (as appropriate) [34–36]. To

date, several studies have showed acceptable short- and long-term QoL outcomes (12- and 24-

month follow-up) in a selective group of patients with OPSCC who have undergone primary TORS

[37,38]. In addition, the functional swallowing outcomes following TORS seem promising, as

indicated by two systematic reviews, but more accurate assessments of swallowing function (than

dependency of nasogastric feeding tube) need to be systematically evaluated in prospective studies

[39,40]. Various kinds of questionnaires designed to measure QoL and swallowing outcomes have

been used in the literature, making comparisons across studies difficult to perform. Only one small

retrospective study including two matched patient groups with OPSCC treated by TORS or

radiochemotherapy has showed similar one-year functional QoL outcomes – with the exception of

swallowing, which was significantly better among TORS patients [41]. However, a prospective

longitudinal study assessed profile patient-reported symptoms during radiotherapy or concurrent

radiochemotherapy for head and neck cancer, and showed that overall symptom severity (p < .001)

and symptom interference (p< .0001) became progressively more severe and were more severe for

those receiving radiochemotherapy compared to radiotherapy alone [42]. Fatigue, drowsiness, lack

of appetite, problem with thick mucus in the oral cavity and pharynx, and problems tasting food

were more severe for those receiving radiochemotherapy.

The current national protocol will focus on evaluating the early and long-term recovery

following 1) TORS combined with neck dissection and 2) IMRT±concurrent chemotherapy

with a special focus on post-operative pain, swallowing function, QoL and time to return to

work.

Our primary aim will be based on the questionnaire MD Anderson Dysphagia Inventory (MDADI),

which is invented by the University of Texas MD Anderson Center to quantify the functional

impairments after treatment, which recently has been validated in Danish [43]. This endpoint has

previously been included in a randomized trial comparing radiotherapy to TORS (ORATOR study)

and is currently being used as a primary endpoint in several ongoing trials (for example PATHOS

in UK).


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We define a 10-point difference in composite MDADI score between groups as significant as

this has recently been defined as a clinically relevant difference in clinical trials [44].

Fiberendoscopic evaluation of swallowing (FEES)

FEES is an examination of structural movements in the pharynx and larynx while the patient eats or

drinks different food and liquids of varying consistencies mixed with colored dye. A

videoendoscopic evaluation of swallowing is performed with a transnasal fiberoptic scope and the

degree of aspiration and retention is assessed by using a modified The Penetration Aspiration Scale.

Modified Barium Swallowing Test (MBS)

The MBS test allows for the identification of normal and abnormal anatomy and physiology of the

swallowing function by using a radiograph. This examination involves fluoroscopy of oral and

pharyngeal phases of swallowing food and liquids of varying consistencies mixed with barium

contrast. The MBS will also be scored using PAS score and DIGEST.

MDADI questionnaire

MDADI includes global, emotional, functional, and physical subscales. The MDADI is the first

validated and reliable self-administered questionnaire designed specifically for evaluating the

impact of dysphagia on the QoL of patients with head and neck cancer.

Quality of Life (EORTC QLQ-H&N35 and EORTC QLQ-C30) questionnaires

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire

(EORTC QLQ)- QLQ-C30, a general cancer-specific questionnaire in conjunction with the EORTC

H&N35, a questionnaire designed to assess the QoL of head and neck cancer patients.

Measurement of late toxicity


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Late toxicity grading will be based on the scoring scheme' from Radiation Therapy Oncology

Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC). This

questionnaire will be used to assess the incidence of late toxicity among patients treated with TORS

±adjuvant therapy compared to IMRT±chemotherapy [45].

Method and Study Design

Overall objectives

The current protocol is a nationwide randomized phase II study that aims to investigate the long-

term functional outcomes after primary TORS±adjuvant therapy vs. IMRT±concurrent

chemotherapy for early-stage oropharyngeal squamous cell carcinoma.

Hypothesis: We hypothesise that primary TORS±adjuvant therapy will significantly improve the

QoL at 12 months follow-up compared to IMRT±concurrent chemotherapy.

Endpoints

Primary endpoints

• QoL measured by a composite MDADI score evaluated at 12 months follow-up after

treatment

Secondary endpoints

Late toxicity (evaluated at baseline, 6, 12, 24, 36, 48 and 60 months after treatment)

o RTOG/EORTC Late Radiation Morbidity Score

• Swallowing function (evaluated at baseline, 3 and 12 months follow-up)

o FEES by PAS score

o MBS by PAS score

o Nasogastric tube / percutaneous endoscopic gastrostomy dependency

• QoL (evaluated at baseline, 3 and 12 months follow-up)


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o EORTC QLQ-H&N35 and EORTC QLQ-C30

o MDADI

• DAHANCA forms according to national guidelines

• Weekly (every Wednesday) self-reported visual analogue scale (VAS) score from start of

treatment until no treatment-related pain is recorded by the patient with no need of

treatment-related pain medication.

• Weight (evaluated at baseline, 3 and 12 months follow-up)

• Social outcomes (evaluated at baseline, 3 and 12 months follow-up)

o Time to return to work or failure to do so

• Long term nerve impairment (12 months monitoring period) including nerves at risk during

surgery (spinal accessory, hypoglossal, marginal mandibular branch of the facial nerve,

lingual and vagal nerve)

• Morbidity (bleeding, lymphedema, nerve injury) after staging neck dissection performed

prior to TORS or IMRT and concurrent chemotherapy

• Survival rates (time from randomization to survival endpoint) up to 5 year follow-up

o Overall survival, disease-free survival and disease-specific survival

• Recurrence rates (time from randomization to recurrence endpoint) up to 5 year follow-up

o Loco-regional recurrences (in same T-site or N-site as initial cancer localization) and

distant recurrence

Inclusion criteria

1. 18 years or older

2. Able to provide informed consent

3. ECOG/WHO performance status 0-2


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4. Histologically confirmed oropharyngeal squamous cell carcinoma (exclusively tonsils and

base of tongue tumours) with known p16 status

5. Clinical tumour stage T1-2 according to UICC, TNM classification, 8th edition.

6. Clinical nodal stage: N0-1 according to UICC, TNM classification, 8th edition, however in

p16 positive patients with unilateral metastasis, we only include a N-site up to a maximum

of 3 cm in greatest diameter according to pre-operative imaging.

7. Diagnostic imaging (CT/MRI) performed within 14 days at time of randomization.

8. A tumour that is considered resectable according to MRI, clinical examination and/or

ultrasound

Exclusion criteria

1. Serious medical comorbidities or ECOG/WHO performance status >2. Other

contraindications to radiotherapy, chemotherapy or surgery

2. Inability to attend full course of radiotherapy or follow-up visits in the outpatient clinic

3. Distant metastasis

4. Clinically and radiologic signs of nodal extracapsular extension

5. Previous radiotherapy of the head and neck

6. Previous head and neck cancer

7. Significant trismus (maximum inter-incisal opening ≤ 35mm) [46]

8. Unable or unwilling to complete QoL questionnaires

9. Posterior pharyngeal wall involvement

10. Pregnancy


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Study design

This is a randomized (2:1) phase II trial comparing the experimental arm TORS ±adjuvant therapy

to the control arm IMRT±concurrent chemotherapy in the treatment of early stage OPSCC.

Please see the attached study design on figure 1.

Randomization at DAHANCA Secretariat

All patients who are eligible for protocol enrolment will receive written and oral protocol

information and have the right to read the protocol information for at least 24 hours before they

provide an informed consent. After informed consent has been given by the patient, a trial

investigator or doctor at the respective recruiting centres will send a fax to the DAHANCA

Secretariat which is responsible for the randomization key to either experimental or control arm.

The DAHANCA will reply the doctor or investigator with the result of the randomization.


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Treatment plan

Patient recruitment and clinical investigations prior to treatment

The trial will be implemented in all recruiting Danish head and neck cancer centers who meet the

quality criteria for joining the trial (see below). Patients are referred directly from primary care or

from other hospital departments including ear, nose and throat and oncology departments. The first

consultation and clinical examination of the patient will be in the outpatient clinic, in a closed

consultation room and will be undisturbed.

A TORS surgeon (investigator) from each center will assess the surgical eligibility of patients who

fulfill the inclusion criteria as stated in the protocol. Clinical examination includes palpation of the

base of the tongue and tonsils in the outpatient clinic (in awake patients) or under general

anesthesia, evaluation of infiltration in surrounding structures and ultrasound scan of the neck.

Radiologic procedures include staging magnetic resonance imaging (MRI) scan of the pharynx and

ortopantomography (or CT reconstruction). Chest x-ray or PET-CT is also included to exclude lung

metastasis. Tumour resectability is assessed on the MRI and clinical examination. The surgeon will

assess the extent of the tumour, with regards to involvement into surrounding structures including

bone, in- or extrinsic tongue musculature. The patient will be excluded if the tumour has direct

contact or is in close proximity to the carotid arteries where a 2mm free margin is not possible to

obtain. Furthermore it requires careful dissection and flap reconstruction and should therefore be

avoided.

Prior to treatment, all patients will be reviewed and examined at a multidisciplinary team

conference (MDT) with head and neck surgeons, oncologists, and radiologists. A clinical oncologist

and a ENT surgeon, respectively, are responsible for the inclusion of patients. They are also

responsible of providing written and oral information to patients that are deemed eligible for

inclusion and will answer any inquires if needed.

The patient has the right to obtain a minimum of 24 hours to reflect over the decision and before a

signed informed consent is given. The patient has the right to invite a friend or a family member as

an assessor during the consultations. After signed informed consent is provided, a fax will be sent to

the DAHANCA Secretariat which is responsible for randomizing the patients.


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All participating patients will be treated in accordance with the national Danish fast track specific

for head and neck cancer [47]. Danish law states that a patient should undergo surgical treatment or

primary radiation within 14 days days of informed consent of treatment plan established at a

multidisciplinary team (MDT) conference. In addition, the maximum number of days allowed from

referral to the ear, nose, and throat department to the start of treatment is 28 calendar days for

surgical treatment and 32 calendar days for IMRT±concurrent chemotherapy.

Experimental arm: Neck dissection and Transoral Robotic Surgery

Preoperative work-up:

Patients are seen in the clinic 1-2 weeks before surgery for a standard work-up including a general

clinical examination, consultation with a general anaesthesiologist as well as a pre-admission talk

with a ward nurse. Laboratory tests, electrocardiogram (ECG) and x-ray studies are performed

when indicated. The TORS-surgeon is responsible for the pre-operative resection planning. At the

time of inclusion all patients will have had a clinical examination as described above. They are then

booked for surgery within 14 days after inclusion and randomization.

Staging neck dissection

Neck dissection will be performed on all patients with cN+ within 8 days prior to the planned

TORS. This is to ensure that final pathology can be assessed in order to stratify the patient for

TORS or IMRT±concurrent chemotherapy.

For patients with cN0, neck dissection can be performed either before (within 8 days) or

concurrently (same day procedure) with TORS.

Patients with a primary palatine tonsil cancer, who are included in the experimental arm, will

undergo ipsilateral neck dissection of lymph node levels II-IV. Patients with a primary base of

tongue cancer or with significant involvement of the tongue base or the soft palate will be offered a

bilateral neck dissection including levels II-IV. Significant involvement is defined as more than

1cm macroscopically or on imaging. The neck specimen will be divided into the different neck

levels. Neck levels are defined according to the DAHANCA group from 2013 [48].

Pathologic assessment of the neck dissection specimen

The number of involved lymph nodes will be assessed as well as the presence of extra-capsular


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extension. If the neck specimen contains < 10 lymph nodes, a total embedding of the remaining fat

tissue will be performed. The pathology assessment of the neck specimen prior to TORS will be

performed within 8 days.

Transoral Robotic Surgery

The surgical robot

The recruiting centre is required to have a da Vinci surgical system (Intuitive® Surgical, Sunnyvale,

CA, USA). The surgical cart consists of three 5 or 8 mm endo-wrist arms including a 3D camera

endoscope, a ”Maryland dissector” and a ”Monopolar with spatula tip”.

Day of surgery:

The peri-operative management of bleeding consists of mono/bipolar electrocautery while larger

vessels are ligated with hemoclips transorally. In addition, ligation of the ipsilateral lingual artery

and/or pharyngeal ascending artery is performed during the neck dissection if necessary in case of

transoral exposure of vessels during tumour dissection.

After resection, the primary tumour is oriented and pinned on a corkboard using different colored

pins to indicate anatomical direction. The surgeon evaluates the macroscopic margins, and in case

of questionable free margins, large supplementary resections including perioperative frozen section

histology are performed. The supplementary resection specimens are oriented according to the

primary tumour specimen, and are subsequently sent to the pathology laboratory for final

pathologic evaluation performed by head and neck pathologists.

Oropharyngeal reconstruction of the soft palate may be necessary and in these cases, a local

muscle-mucosal flap or fat transpositions can be used.


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Length of hospital stay

After the surgery, the patients are transferred to the recovery room and when appropriate to the

ward. The patients will be hospitalized for at least four days before discharge and will be discharged

when conditions permit and when necessary study parameters have been assessed.

Pathologic assessment of the resected tumour specimens

The surgical margins are inked with different colors corresponding to the different anatomical

directions. The specimens are formalin-fixed for at least 24 hours before further macroscopic

evaluation. In cases of a visible tumour, sections will be taken from the tumor with relation to the

closest margin of all of the corresponding anatomical sites together with the closest deep margin. If

no macroscopic visible tumour is evident, the entire specimen must be cut into 2–3 mm sections

perpendicular to the surgical margins and totally embedded as described previously [49]. The

resection margins of the primary tumour are evaluated microscopically and assessed by measuring

the shortest distance (mm) from tumour to all edges of the surrounding tissue margins (including

deep margin) specified by the surgeon. In formalin fixated paraffin embedded tissue, surgical

margins of 2 mm or above are considered free, up to 2 mm as close, and 0 mm as involved. Any

margin with a free supplementary tissue is considered free. These margins can be obtained at the

primary surgery or at a secondary procedure.

Tumours are classified as non-keratinizing squamous cell carcinoma (NKSCC) or keratinizing

squamous cell carcinoma (SCC); grading and subtyping are done according to the World Health

Organization classifications of head and neck tumours/© International Agency for Research on

Cancer [50]. The primary tumour will be analyzed for HPV-DNA and p16 (unless this is obtained

previously from tissue biopsies). Polymerase chain reaction (PCR) is utilized for the detection of

HPV-DNA. p16 immunohistochemistry is performed on all specimens. p16 positivity is defined as

a strong and diffuse nuclear and cytoplasmic reaction in more than 70% of the tumour cells

according to the EORTC and RTOG.


22

Adjuvant radiotherapy±concurrent chemotherapy

Postoperative adjuvant therapy will be offered to the individual patient based on a final pathology

result. If adjuvant therapy is indicated, the patient will always be referred to an oncologist who must

inform about the therapy, prior to a final decision. It is imperative that information about adjuvant

therapy is given by a clinical oncologist. Radiotherapy consists of IMRT treatment and will be

offered alone based on following indications:

Nodal site:

• More than two lymph node metastases

• Two lymph node metastases and both above 1 cm in diameter.

• Any pN+ with ECE

• A neck dissection nodal yield of less than 10 lymph nodes per side (after total embedding of

the remaining fat tissue)

Tumour site:

• Involved or close resection margins of < 2 mm if free margins was not obtained after

supplementary resections per-operatively or after re-resection in a secondary procedure.

• In case of stage migration to T3 or T4, in an otherwise R0 patient, adjuvant therapy will be

offered based on a postoperative consultation between the patient, the surgeon and an

oncologist.

Control arm: Primary radiotherapy

Patients in the control arm will be treated according to the most recent DAHANCA guidelines [48].

All centers should use a GTV-CTV margin, as described in the guidelines. The elective volumes are

levels II-III bilaterally, however, in well lateralized tumors unilateral treatment. In case of nodal

involvement the volume should also include level IV on the involved side(s). Delineation and dose

to organs at risk (OARs) should follow the most recent DAHANCA guidelines. Patients should be

treated with Intensity-Modulated Radiotherapy.


23

Patients with T1N0 tumors are offered accelerated radiotherapy to 66 Gy/33fractions with

concurrent nimorazole. Patients with T2N0 are offered either accelerated radiotherapy to 66

Gy/33fractions with the option of weekly cisplatin to fit patients or hyper-fractionated accelerated

radiotherapy to 76 Gy/56fractions both with concurrent nimorazole. Patients with T1-T2, N1 are

offered accelerated radiotherapy to 66 Gy/33 fractions and nimorazole with the addition of

concurrent weekly cisplatin 40 mg/sqm to fit patients.

Experimental arm: Post-operative radiotherapy (following primary TORS or staging neck

alone)

As described above in the primary TORS arm the indications for post-operative radiotherapy are: a)

Primary resection margin < 2mm b) Extra-capsular extension (ECE) c) Involved lymph node count

>2 d) Involved lymph node count = 2 and both >10mm e) Ipsilateral neck dissection with < 10

lymph nodes. The post-operative radiotherapy should commence within four weeks after surgery.

In case of insufficient resection margin (<2mm) or ECE, the post-operative radiotherapy should be

supplemented by concurrent weekly cisplatin (40mg/sqm) to fit patients, according to the

DAHANCA guidelines for oral cavity tumours.

a. CTV1: Macroscopic tumor, preoperative tumor with a resection margin < 2mm or lymph

nodes in case of ECE defined by preoperative volume with an isotropic margin of 5 mm corrected

for relevant anatomical boundaries. In case of uncertainty the margin can be expanded in specific

directions. In case the added margin includes air or natural anatomical boundaries, the margin can

be reduced accordingly.

b. CTV2: CTV1 with an isotropic margin of 5mm, adjusted if the added margin includes free

air or natural boundaries (eg. bone). Can on an individual basis be expanded to include other high-

risk anatomical regions.


24

In case there is no CTV1, e.g. in radically resected patients (R0), CTV2 is the pre-operative target

(primary tumor and nodes) contoured using co-registration of pre-operative imaging with an

isotropic margin of at least 10mm. Although the indication for post-operative treatment is in the

nodal area alone, the primary tumor area needs to be included. In case of uncertainty the margin can

be expanded in specific directions. In case the involved nodes cannot be defined on preoperative

scans, the involved level is included.

c. CTV3: should be used to cover the remaining surgical area and the elective neck. In case of

pN0 the volume should include levels II-III bilaterally or unilaterally in case of lateralized tumor

without involvement of midline organs. In case of nodal involvement the volume should also

include level IV on the involved side(s). In case of posterior wall involvement of the primary tumor

the retropharyngeal lymph nodes on both sides should be included in CTV3. CTV3 should expand

at least 2 cm superiorly/inferiorly over any nodal GTV. In case of the primary tumor involving oral

cavity level IB should be included. In case of nodes involving the SCM, the whole SCM shall be

included 2cm superiorly/inferiorly over the muscle involvement.

Note: If the indication for post-operative radiotherapy is in the T position alone, after neck

dissection without factors indicating post-op radiotherapy, elective neck radiotherapy can be

excluded in pT1 and pT2 tumors.

Compliance Criteria

Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for the

treatment break(s). Treatment breaks should be allowed only for resolution of severe acute toxicity

and/or for intercurrent illness and not for social or logistical reasons, and should be dealt with as

described in the radiotherapy guidelines.


25

Radiotherapy Quality Assurance Reviews

Quality assurance reviews should be performed before the third treatment fraction by a team from

another head-neck oncology center consisting of one physicist and one oncologist. The patient

specific review will address the following points according to the DAHANCA guideline: CTV and

OAR delineation, target dose coverage, OAR dose sparing and treatment length.

The specific procedure and logistics of the QA review will be described by the DAHANCA QA

group in a separate supplement to the protocol.

Quality requirements for recruiting centre

The recruiting centre has to be able to perform both TORS and IMRT including the ability to

perform the necessary examinations in compliance with the current protocol including MBS and

FEES. A sufficient learning curve in TORS is met when a minimum of 15 TORS cases has been

performed with free margins (without significant complications). At least 5 of these cases have to

be base of tongue resections and 5 radical tonsillectomies. This is to ensure that the level of

experience with TORS is adequate, which is important in terms of making a correct preoperative

assessment of patients for eligibility. A correct pre-operative assessment of the tumour size and

anatomical location is a key feature in order to perform radical surgery and minimizes the risk of

perioperative complications.

In addition, each oncological centre is required to complete the radiotherapy treatment plans in

compliance with the protocol.


26

Study Parameters and Evaluations

All primary and selected secondary parameters will be analysed after primary endpoint at 12

months after treatment. These parameters including survival outcomes will however continuously

be registered and analysed after 12 months at standard follow-up visits including registration of data

in DAHANCA forms.

The following parameters and evaluations will be investigated and collected throughout the entire

study period.

Baseline evaluations

All included patients will undergo baseline evaluations within 2 weeks after randomization

including swallowing function evaluations with FEES and MBS, both of which are real-time

objective measures using PAS score schema. MBS is performed at the department of radiology

including a co-investigator or occupational therapist and radiologist. A FEES is performed by an

investigator or co-investigator from the department of Otorhinolaryngology with or without an

occupational therapist. Both examinations will be recorded and stored for later review and

secondary evaluations if needed. Mouth opening will be measured using Therabite range of motion

scale [51].

QoL will be assessed using three scientifically validated questionnaires in Danish (MDADI,

EORTC QLQ-H&N35 and EORTC QLQ-C30). These questionnaires will be completed in the

outpatient clinic/ward under supervision of a research nurse or by an investigator/co-investigator.

All patients will perform a VAS score assessment prior to treatment and will be evaluated twice

daily (12:00 and 18:00) during rest and during eating/swallowing. A research nurse or medical

doctor will be responsible for teaching and supporting the patient in recording the VAS score and

will also introduce a VAS score diary which the patient will utilize at home following discharge.

A full clinical examination of nerve functionality will be assessed prior to treatment. The following

nerves are of interest: spinal accessory, hypoglossal, marginal mandibular branch of the facial


27

nerve, lingual and vagal nerve. The function of the nerves will be assessed by a medical doctor from

the investigator group.

Patient demographic and clinical characteristics

Includes: age, gender, weight, social and work status, tobacco and alcohol consumption as well as

tumour-node-metastasis (cTNM) staging (UICC, TNM classification, 8th edition). Comorbidity will

be assessed using the Charlson Comorbidity index which is obtained in a Danish translated version

from DAHANCA [52].

Surgical parameters

• Type of surgical procedure

• The need for re-resection.

• Duration of surgical procedure

• Type of reconstruction (if performed)

• Extent of neck dissection (ipsi- or bilateral and neck levels)

• Peri-operative complications - including nerve injury (spinal accessory, hypoglossal,

marginal mandibular branch of the facial nerve, lingual and vagal nerve), bleeding (ml) or

injury to the thoracic duct.

• Length of hospital stay

• Speech impairment (due to insufficient velopharyngeal function) and consist of a perceptual

evaluation by a medical doctor.

• Infections (i.e. pneumonia, infection at surgical site) – verified by radiological examination

or laboratory tests including blood cultures or blood samples (increase in leukocytes/CRP).

• Presence of pharyngocutaneous fistula or abscesses, chylous leak

• Tracheotomy rates


28

IMRT±concurrent chemotherapy parameters

Parameters as described in the Radiotherapy guidelines in DAHANCA, including target coverage,

target volumes, dose levels, number of elective lymph node levels included, dose to salivary

structures, pharyngeal constrictors and the oral cavity. Chemotherapy cycles, dose and length of

possible admissions and complications; i.e. infections, leucopenia and bleeding,

Pathologic parameters (primary tumour specimens)

• Histological tumour type and level of differentiation if relevant assessed at the invasive front

of the tumour according to WHO classification 2017 [50].

• Description of the invasive front of the tumour: cohesive or non-cohesive

• Size of primary tumour (microscopic) in two dimensions (mm)

• Deepest infiltration and thickness of tumour (mm)

• Tumour’s relation to the tonsillar lymphoid tissue (tumour confined to the tonsillar

lymphoid tissue or breaking through of it and infiltrating the surrounding soft tissue)

• Resection margins of the primary tumour = shortest distance (mm) from tumour to all edges

of the surrounding tissue margins (including deep margin) specified by the surgeon.

• Shortest distance (mm) from dysplasia/carcinoma in situ to all edges of the examined

surrounding tissue margins

• Presence or absence of perineural tumour spread and vascular invasion

• Presence or absence of desmoplastic reaction.

• HPV-DNA and p16 status (unless this is obtained previously from tissue biopsies)

Pathologic parameters (Lymph node specimens)


29

• Number of lymph nodes in each anatomic neck level, where level II-III are grouped as

one.

• Number of positive lymph nodes in each neck level

• Tumour diameter (mm) of metastasis in all positive lymph nodes

• Presence of microscopic nodal extracapsular spread, and is graded as:

- positive: when macro- or microscopic extension of tumor breaching the lymph

node capsule

Based on the above parameters, a pathological TNM (pTNM) will be determined (UICC, TNM

classification, 8th edition).

Morbidity parameters

Delayed side effects in the treatment of oropharyngeal cancer may appear or progress much later

after 12 months after initiation of treatment. Thus, long periods of observation is required to assess

effects of treatment by ECOG/EORTC scheme [45]. Registration of toxicity will be performed at

baseline, 6, 12, 24, 36, 48 and 60 months after treatment by Late Radiation Morbidity Score and by

regular follow-up up to five years after randomization.

Long term nerve impairment will be monitored in a 12 months monitoring period including nerves

at risk during surgery (spinal accessory, hypoglossal, marginal mandibular branch of the facial

nerve, lingual and vagal nerve).

Disease control and survival parameters

Registration of loco-regional recurrence, distant recurrence, overall survival, disease-free survival

and disease-specific survival by regular follow-up after day of randomization. The per protocol

parameters are evaluated up one year after the treatment. However, all patients are scheduled to

have a clinical follow-up for at least five years after treatment. Survival and recurrence data will be

extracted from the electronic database or the DAHANCA database.


30

The definition of local, regional or distant recurrences versus new primary, is defined Table 2,

Addendum.


31

Follow-up evaluations

Control arm (IMRT±concurrent chemotherapy) and adjuvant therapy:

All patients who are treated in the control arm will be seen weekly during radiotherapy. They will

follow the protocol follow-up described below from end of radiation therapy.

Patients who are eligible for adjuvant therapy will follow the same protocol follow-up.

Experimental arm (neck dissection and TORS±adjuvant therapy):

Prior to surgery, the patients will participate in a multidisciplinary team conference including a head

and neck surgeon and an oncologist to be informed about the indication for adjuvant radiation

therapy.

Postoperatively after neck dissection / staging neck prior to TORS or adjuvant therapy:

Morbidity in terms of peri- and postoperative complications including nerve injury, bleeding and

lymphedema will be evaluated and recorded.

Postoperatively after TORS

Day 1-4 – Hospital ward:

The patients will be examined by an occupational therapist or co-investigator and a doctor to

determine the need of nasogastric tube and refer to a municipal rehabilitation programme when

appropriate.

Day 13-15 – Outpatient clinic:

The patients are given the pathology result including whether free margins were achieved. Clinical

examination is performed in order to determine any signs of infection or other complications as

stated above. When indicated, patients are referred to the oncology department for adjuvant therapy

according to our protocol. Duration of tube dependency will be registered.

Week 4 – Outpatient clinic

Clinical assessment of T- and N-site, registration of adverse events.


32

Protocol follow-up for both arms:

DAHANCA forms

All DAHANCA forms have to be completed according to the national guidelines

Pain assessment

All patients will be evaluated after primary treatment in terms of pain using the visual analogue

scale (VAS). The pain medication regimen after surgery is the same across all centers. Thus, the

patient will continue to perform the VAS score twice once weekly every Wednesday (during rest

and while swallowing) from start of treatment until no treatment-related pain is recorded by the

patient with no need of treatment-related pain medication. The patients may contact the research

nurse (or vice versa), so reliable VAS score can be performed.

Month 2 – MDT conference ±7 days

• Duration of nasogastric tube / percutaneous endoscopic gastrostomy dependency

Month 3 ±14 days

• QoL questionnaires (EORTC QLQ-H&N35, EORTC QLQ-C30 and MDADI)

• Toxicity: RTOG Late Radiation Morbidity Score

• FEES and MBS in both treatment arms.

• Mouth opening will be measured using Therabite range of motion scale.

• Clinical assessment of T- and N-site, registration of secondary parameters and adverse

events

Month 6 ±14 days



events

12 months ±14 days


33

• QoL questionnaires (EORTC QLQ-H&N35, EORTC QLQ-C30 and MDADI)


• FEES and MBS will be re-evaluated after 12 months±1 month in both treatment arms.

• Mouth opening will be measured using Therabite range of motion scale.


events

Standard clinical follow-up after the study

According to our national guidelines, the patients are scheduled to have a clinical follow-up every

six months post-operatively up to two years and every year thereafter up to a total of five years of

follow-up.

Time to return to work as well as changes to the working situation will be registered at initial

clinical examination and the all clinical follow-ups after treatment.


34

Study sample size considerations

Type of randomization

Included patients will be randomized in 2:1 ratio, in which the probability that a patient is assigned

to the experimental treatment arm is 2/3. The 2:1 randomization is chosen to ensure acquisition and

volume in the experimental arm, and to ensure a sufficient sample size for a proxy comparison of

the experimental arm with a historical cohort treated (chemo)radiation for secondary endpoint

analysis of recurrence pattern and disease control. The randomization will be performed centrally

by DAHANCA.

Sample size and statistics

Sample size:

The study is planned using of a continuous response variable from independent control and

experimental subjects with 0.5 control(s) per experimental subject. In a previous study the response

within each subject group was normally distributed with standard deviation 17. It has been argued

that a difference in 10 or more on the MDADI scale should be considered clinical relevant [44]. If

the true difference in the experimental and control means is 10 in the MDADI

composite score, we will need to study 92 experimental subjects and 46 control subjects to be

able to reject the null hypothesis that the population means of the experimental and control groups

are equal with probability (power) 0.9. The Type I error probability associated with this test of this

null hypothesis is 0.05.

The model used to generate expected survival curves will be based on multivariate analysis of a

database of previously treated patients (ref to some of our database publications). The multivariate

Cox model can be used to generate an expected survival curve by taking the mean of all prognostic

factors for the trial patients and plot the curve corresponding to the Cox formula, 𝑆(𝑡) =

𝑒𝑥𝑝−Λ(𝑡)𝑒+, where S(t) is the survival function, L(t) is the baseline cummulative hazards function

of the model with fitting parameters b (log hazard ratios) and X represents the mean of the risk

factors in the patients included in the TORS arm of the trial. The predicted 2-year loco-regional

freedom from recurrence can now be compared to the observed Kaplan Meier curve for the trial


35

patients and extract the relative risk of loco-regional recurrence after 2 years. This can be compared

to the model prediction based on historical controls. Confidence bands on the expected outcome

curve will be obtained by bootstrap resampling or other published methods [53]. The RT arm

patients of the trial will be compared to the historical controls in the same way to assess the

calibration, albeit with the expected limited power of this smaller series.

The patients in the trial will be analyzed according to the intention-to-treat principle regardless of

the stratification of patients in the experimental arm. This method allows us to draw accurate

(unbiased) conclusions regarding the effectiveness our intervention.

Stratification for p16

We will stratify for p16 at time of inclusion to avoid an uneven distribution of p16 in the

experimental arm compared to the control arm.

Estimated study period

The national protocol is estimated to start early 2018 with an estimated completion date in June

2021. However, the study period is based on the inclusion of patients.

Based on published data from Copenhagen University Hospital (Rigshospitalet), approximately 175

patients are diagnosed annually with OPSCC within the eastern regions of Denmark, accounting for

an approximately 45% of all cases in Denmark. A recent TORS study from Rigshospitalet included

30 consecutive patients (cT1-2 and cN0-N1) treated from September 2014 to January 2016. Based

on these data, it is estimated that a total number of 35 patients will be included per year at

Rigshospitalet. On a national scale, all recruiting centres are estimated to include an estimated 85

patients a year with a clinical TNM stage stated in our inclusion criteria.


36

Management of data contained in clinical trial

Data collection and management

All questionnaires and necessary forms will be accessible from the DAHANCA website.

An application regarding the management of data in the trial will be sent to the Danish Data

Agency.

At the time of inclusion, an electronic Case Report Form (CRF) in REDCap is used to collect data

from each participating patient. All relevant protocol parameters including adverse events will be

registered in the CRF. All investigators are obliged to ensure that all data are acquired. A CRF

checklist will further assist the investigators during the clinical trial We will collect clinical data

(including history, pathology and previous scans) from the patient medical records, which will be

used for research purposes and for quality control during the study.

All the acquired data will be entered into an electronic database using “RedCap”. Data is stored and

handled in accordance with the Danish Data Agency regulations, EU's General Data Protection

Regulation (GDPR) and in compliance with the national data agreement between the study

locations. No data will be sent to third parties outside Denmark.

DAHANCA registration

All mandatory clinical data (on-study, primary treatment, control during radiotherapy and follow-

up, recurrence and death) will be entered in the DAHANCA database for all patients. Specific

protocol parameters which are not included in the DAHANCA forms will however only be

registered in the electronic trial database using REDCap.

Good Clinical Practice (GCP) and data monitoring

During the trial, the GCP unit in Aarhus will monitor the study trial according to the given protocol

and the current legislation. The monitoring period will consist of the first 12 months of inclusion

until the primary endpoint. Along the study, GCP will perform routine control visits at each center

to ensure that the necessary data are collected and entered in the electronic case report form in

REDCap.

The subsequent follow-up period and data registration after 12 months will be ensured and

monitored by the primary study investigators.


37

The primary contact person is Birgitte Horst Andreasen.

Contact details:

GCP-enheden ved Aalborg og Aarhus Universitetshospitaler

Olof Palmes Allé 15

8200 Aarhus N

[email protected]

Tlf: + 45 78 41 39 51

Data Management Plan

A Data Management Plan (DMP) will outline the necessary requirements of data collection and

management, including how data will be stored and analyzed. The DMP will be based on the

obligations and requirements from the Danish Data Protection Agency, EU’s GDPR and the

National Research Ethics Committee.

Collaboration agreement between investigator groups

Rigshospitalet is responsible for establishing a collaboration agreement between all participating

centres and investigators. All participating data collectors are legally bound to the collaboration

agreement.

Ownership of data

The DMP will include information about how data will be shared, including when the data will be

accessible, how long the data will be available, how access can be gained, and any rights that the

data collector reserves for using data.

Any transfer of ownership of the data should be reported to the appropriate authority(ies), as

required by the applicable regulatory requirements.

All authorities who need to access data by law will be permitted data access from the REDcap

database. If other research groups wish to access the any of the research data, they may contact the

primary investigators for further data agreement.


38

Publication of results

Positive, negative and inconclusive results of the trial will be submitted for publication in peer-

reviewed international journals, at www.clinicaltrials.gov or www.clinicaltrialsregister.eu. Any

publication based on this study will abide by the Vancouver rules. All publications which include

data collected from recruiting centres are required to have co-authorships of minimum two ENT

surgeons, two oncologists and one pathologist. The order of the authors will be listed according to

volume of patients included at each centre.

Investigators from Aarhus University Hospital will investigate the cost-effectiveness and

socioeconomic outcomes with the aim of comparing cost-utility and quality-adjusted life years for

TORS and IMRT.

Investigators from Rigshospitalet will investigate Days Alive and Out of Hospital and factors

related to hospitalization rates after TORS.

All addendum protocols must only be published after the results of the main protocol has been

published.

Publications regarding the primary endpoint and survival/recurrence outcomes

The trial sponsor (C.v.B) is entitled to have the last authorship while principal investigator (N.R.)

and main contributor of the protocol (H.I.C) from Rigshospitalet are entitled to be the primary

authors. The publications will also include authors who have contributed substantially according to

the Vancouver rules.

Registration of protocol at clinicaltrials.gov

The protocol will be registered at the public database clinicaltrials.gov

Interim publications of secondary endpoints

Interim publications regarding specific secondary outcomes which have been gathered from all

centres will also be include the co-authors as stated above, as well as other investigators who have

contributed substantially according to the Vancouver rules.


39

Positive, negative and inconclusive results of the trial will be submitted for publication in peer-

reviewed international journals, at www.clinicaltrials.gov or www.clinicaltrialsregister.eu. The

results will also be presented at national and international conferences. All publications and

presentations will follow a signed authorship agreement by the various investigators.

As stated in the informed consent form anonymised trial patient photos or scans can be used in

publication and presentations.


40

Complications and adverse events

The side effects listed below are based on the current literature as well as our own experience with

TORS. Based on current literature we expect that primary treatment with TORS as described in this

protocol is safe. Smaller studies have shown that there are fewer complications following primary

surgery±adjuvant treatment compared to primary radiotherapy [17].

In the study, the clinical investigators are obliged to register expected and unexpected adverse

events (AE), adverse reactions (AR), and serious adverse reactions (SAR) or events (SAE) that may

arise during the trial.

Registration of AE, SAR and SAE: will be registered up to 30 days after ended treatment.

Registration of AR: the monitoring of AR will be registered until five years of follow-up.

A list of all presumed expected and unexpected SAE must be reported once yearly to the

Regional Committee on Health Research Ethics using a safety reporting form. SAE is defined as an

event after treatment (surgery, radiation or chemotherapy) that results in death, is life-threatening,

and requires hospitalization or prolongation of existing hospitalization or results in persistent or

significant disability.

All presumed SAE and SARs will be discussed among the investigators in terms of

classification and whether the investigator is obliged to report this.

General complications

Almost all types of surgery including TORS are associated with a bleeding risk both peri- and

postoperatively. There is also a risk of post-operative wound infection. Events recorded during the

study period starting from the day of surgery.

Complications regarding TORS

All patients experience pain upon swallowing postoperatively, which requires medical treatment.

This usually subsides within 3 weeks. Following radical resection of the tonsil some patients will

experience closure insufficiency towards nasopharynx i.e. rhinolalia aperta. This leads to a

characteristic hyper-nasal speech as well as difficulty swallowing especially liquids as it can be

propelled up into the nasal cavity instead of down into the oesophagus. This is often only a


41

temporary complication related to the healing process lasting about two to three weeks. Chronic

defects might require reconstructive surgery.

Dysphagia is primarily a problem during initial healing (1-3 weeks). During this period aspiration

pneumonia is a risk. Moreover, patients often experience a sensation of increased and thick saliva

which is not necessarily visible at the clinical follow-up. It normally subsides within the first 3-6

months and is not described as a major side-effect by the patients.

Patients may also develop trismus. This is relatively rare in primary surgery without reconstruction

[54].

In certain cases of postoperative bleeding it can be necessary to perform a tracheotomy to secure the

airways during the healing process [16].

In addition, there is a risk of reduced taste and sensation of the tongue (lingual nerve), which is

partly due to the use of a mouth gag during surgery that applies significant pressure on the base of

the tongue and can directly affect the lingual nerve. Permanent damage can occur if the nerve is

either accidentally or deliberately dissected. Deliberate dissection of the lingual nerve occurs in the

context of a tumour that involves or alternatively is located very close to the nerve. However, the

nerve is situated profound to the normal dissection plane making it a relatively rare complication.

Damage to the function of the tongue (hypoglossal nerve) in relation to tumour resection is not

common, but as described below, it can be damaged during neck dissection.

Some patients experience both short and long-term symptoms of chronic pharyngitis, characterized

by the sensation of increased pharyngeal mucus.

Complications regarding neck dissection

Risks associated with neck dissection are well known. After neck dissection, some patients may

develop scar tissue but most often the incision heals well. There is a risk of damaging the lower

marginal branch of the facial nerve. However, this may be avoided by performing careful dissection

with the use of nerve monitoring throughout the dissection. If the nerve is damaged, the patients can

develop asymmetrical mouth movements particularly when smiling but also at rest as the patient

cannot depress the corner of the mouth on the damaged side.


42

There is a risk of damaging the greater auricular nerve, which is a sensory nerve. If damaged, this

causes loss of sensation in an area around and including the ear lobe.

The spinal accessory nerve runs in close proximity to lymph nodes that are removed in a neck

dissection. Although rarely damaged because of its large calibre, temporary nerve dysfunction is not

uncommon. Permanent injury will affect the ability to raise the arm above the head on the damaged

side as well as atrophy (wasting) of muscles in the shoulder which can also cause pain.

Complete or partial damage of the hypoglossal nerve, which innervates the muscles of the tongue, is

rare especially in N0 and N1 disease.

Complications regarding IMRT and adjuvant treatment

Treatment in the control arm (IMRT±concurrent chemotherapy) is the standard treatment in

Denmark, and information is given in accordance with the normal procedure for these patients.

Side-effects during or after radiation can be acute or chronic (short or long term) and include:

• Inability to consume any solid food – liquids only (acute)

• Mouth sores or fungal infection (acute)

• Dental problems (acute / chronic)

• Pain during swallowing (acute / chronic)

• Dry mouth or throat - loss of saliva partially or almost totally (acute / chronic)

• Sore and swelling of the throat (acute / chronic)

• Miscoloured, red irritated skin (acute /chronic)

• Difficulty swallowing (acute /chronic)

• Loss or major changes to sense of taste and/or smell (chronic)

• Problems with opening of the mouth due to stiff jaw muscles and joint (chronic)

• Tension of the skin of the throat (chronic)

• Fatigue (chronic)

• Reduced production of thyroid hormones (chronic)


43

Rare complications include: Osteradionecrosis

Very rare complications include injury of the spinal cord resulting in numb areas and pain in arms

and legs.

Concomitant chemotherapy tend to increase the acute side effects of the radiation in addition to a

risk of nausea, vomiting and numb areas and pain in arms and legs. Rarely it may cause hearing

problems or tinnitus.

Respect for the patients physical and mental integrity and privacy.

All patients included in this study are protected by EU’s GDPR.

All data is treated confidentially and each recruiting centre is responsible of managing the data safe

and in compliance with the Danish Data Protection Agency. The collected data will be kept for 10

years after the completion of the study.

Ethical considerations

The trial will be conducted according to the Declaration of Helsinki. An application will be sent to

the Regional Committee on Health Research Ethics.

All trial patients will be treated according to the treatment plan and randomization code. However,

there is no guarantee that every patient will benefit from participating in the trial in terms of the

experimental arm. TORS has shown good morbidity and oncological outcomes in several

retrospective and prospective international non-randomized trials. Most recently we have showed

that it is a safe and feasible procedure to perform radical surgery at a Danish head and neck cancer.

Thus, the benefits of offering TORS in terms of safety and the potential therapeutic effect for the

patients in the current trial outweighs the risks an side-effects associated to the experimental arm.

If the results of the experimental arm are superior of the control arm, this may lead to a change in

treatment in future, in which TORS can be offered as an alternative to the radiotherapy regime that

is currently the standard in Denmark. In addition to the primary end-point, secondary endpoints in

terms of survival and failure rates are essential to include in the overall conclusion of the trial.


44

In conclusion we think it is reasonable to conduct the trial as we are of the opinion that the overall

benefits of the trial exceed the risks.

Interim analysis

An external and independent assessment committee will assess and monitor the safety of the

surgical treatment after inclusion of 10 patients at each of the including centres. At Rigshospitalet,

consultant and clinical professor Lars Bo Svendsen and consultant Henrik Lajer will act as external

risk-managers. Risk-managers from Odense and Aarhus University Hospitals can also be included

in the assessment committee. This is in order to secure the patients safety early in the trial. The

external risk-managers will assess the following parameters: the ability to obtain free resection

margins on T-site, lymph node yield after neck dissection, need of adjuvant therapy after surgery

and complications including perioperative and postoperative bleeding, nerve injury and death. As a

reference, the published pilot protocol study from Rigshospitalet can be used.

Stopping rules

This trial does not include any stopping rule

Guidelines for participant information and written informed consent

Eligible patients will be informed of the study trial aims and randomization at a consultation where

they will be informed by a clinical oncologist or ENT surgeon. At this consultation the patient will

receive both written and verbal information including the informed consent form. The consultation

will take place in a quiet and undisturbed room. The patient is informed of the trial aim, potential

risks and benefits associated with the trial treatment arms. Procedures and possible side effects and

complications are also explained.

Potential participants will be informed that it is voluntary to participate in the trial, and that they, at

any time and without justification can withdraw their consent to participate without that affecting

their future treatment. The patients are offered 24 hours from the time that oral and written

information is given to sign the informed consent form. The form will contain the patient’s dated

signature along with the dated signature of an investigator. A copy of the signed and dated consent

form will be given to the patient along with the written participant information (if this has not

already been handed out) and the booklet "The patients’ rights in a scientific research project"

published by the National Research Ethics Committee.


45

Informed Consent

All trial patients must sign the consent form to be included in the trial. The signed consent from the

patient give the sponsor of the trial, monitoring committee and relevant authorities direct right to

access the patients’ data. Participation in the trial and the date of inclusion will be documented in

the patients CRF. A member of the investigator team is responsible for ensuring that none of the

enrolled patients undergo any study related investigations or activities before the patient has given

written informed consent.

Insurance

All trial patients will by law be covered by the general insurance for patients treated in the health

care system at the different study locations.

Financial plan

The study protocol was initiated by the Department of Otorhinolaryngology, Head & Neck surgery

and Audiology at Rigshospitalet. Each recruiting head and neck cancer center is economically

responsible for all evaluations and treatments as stated in the collaboration agreement. In addition,

each department of otorhinolaryngology is financially responsible for all HPV-DNA analyses.

If the need for further funding through external funds, companies or similar arises in the study

period, the Regional Ethical Committee will be informed and it will also be added to the patient

information document.

There are no financial benefits for the department or the investigators relating to the trial. No health

professionals involved in the study have any financial disclosures or conflicts of interests related to

the project or in Surgical Intuitive who manufacture the da Vinci Surgical System.

Reimbursements to the patients

No payment or reimbursement will be made to the enrolled patients.


46

PROTOKOL RESUMÈ

1. Projekt titel

Livskvalitet efter robotkirurgisk behandling sammenlignet med strålebehandling hos patienter med

tidlige stadier af mundsvælgkræft: en national randomiseret undersøgelse.

2. Forsøgsansvarliges/sponsors navn og forsøgssted

Forsøget bliver udført på flere hospitaler i Danmark som inkluderer Rigshospitalet, Herlev Hospital,

Næstved Sygehus, Odense Universitetshospital og Aarhus universitetshospital.

Sponsor-ansvarlig for hele forsøget

Øre-næse-halskirurgisk og Audiologisk Klinik, Rigshospitalet, Blegdamsvej 9, 2100

København Ø

Christian von Buchwald, Professor, Overlæge, Dr.med.


Forsøgsansvarlig på Øre-næse-halskirurgisk og Audiologisk Klinik, Rigshospitalet,

Blegdamsvej 9, 2100 København Ø

Koordinator for alle forsøgsansvarlige

Niclas Rubek, Overlæge


Forsøgsansvarlig på Onkologisk Klinik, Rigshospitalet

Jeppe Friborg, Overlæge, ph.d.


mailto:[email protected]


47

Forsøgsansvarlig på Onkologisk afdeling, Herlev Hospital

Jens Bentzen, Overlæge


Forsøgsansvarlig på Onkologisk afdeling, Næstved Sygehus

Mohammad Farhadi, Overlæge


Forsøgsansvarlige på Øre-næse-halskirurgisk afdeling F, Odense Universitetshospital, Søndre

Blvd. 29, 5000 Odense C

Christian Godballe, Professor, Overlæge, ph.d.


Forsøgsansvarlige på Onkologisk afdeling, Odense Universitetshospital, Søndre Blvd. 29, 5000

Odense C

Jørgen Johansen, Overlæge


Forsøgsansvarlige på Aarhus Universitetshospital, Øre-næse-halsafdeling H, Nørrebrogade

44, 8000 Aarhus C

Thomas Kjærgaard, Overlæge, ph.d.

Forsøgsansvarlige på Aarhus Universitetshospital, Afdeling for Eksperimentel Klinisk

Onkologi, NBG, Nørrebrogade 44, 8000 Aarhus C

Jesper Eriksen, Overlæge, ph.d.


3. Forsøgets formål


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Sammenligning af livskvalitet og synkefunktion hos patienter med kræft i mundsvælg der

behandles med robotkirurgisk behandling eller strålebehandling.

4. Forsøgets metode, herunder oplysning om evt. forskningsbiobank

Forsøget er et nationalt randomiseret fase II studie, der randomiserer til henholdsvis robotkirurgi

eller stråleterapi i en 2:1 ratio. Forsøget udføres som en DAHANCA (Danish Head and Neck

Cancer Group). Baseret på statistiske styrkeberegninger er forsøget planlagt til at inkludere 92

forsøgspersoner i behandlingsarmen (robotkirurgi) og 46 i kontrolarmen (stråleterapi).

Strålebehandlingen mod knuden i mundsvælget og halsens lymfeknuder med eller uden kemoterapi

udføres efter de danske nationale retningslinjer og omfanget vil afhænge af kræftstadiet.

Behandlingen strækker sig over 5-6 uger.

Den kirurgiske behandling består af to operationer der kan foretages enten samme dag eller adskilt

med cirka en uges mellemrum. Den ene del består af en robotassisteret operation gennem munden

med fjernelse af kræft i halsmandler eller tungerod. Efter robotoperationen kan der være risiko for

at patienten vil blive tilbudt strålebehandling med eller uden kemobehandling. Dette afhænger af

kræftstadiet, og om der resterer kræftvæv efter operationen. Den anden del består af en

halsoperation med fjernelse af de lymfeknuder. På baggrund af halsoperationen vil det i nogle

tilfælde ikke blive aktuelt at fortsætte med robotkirurgi, og du vil i stedet blive tilbudt

strålebehandling.

Før start af behandling med robotkirurgi eller stråleterapi (baseline) registreres en række kliniske

oplysninger om patienten, der udføres synkefunktion tests og måling af livskvalitet. Patienterne får

udleveret en smertedagbog til scoring af smerter under/efter behandling.

Efter behandling følges forsøgspersonerne tæt det første år, med regelmæssige

synkefunktionsundersøgelser og livskvalitet spørgeskemaer samt registrering af bivirkninger og evt.

alvorlige hændelser i relation til behandling. Synkefunktion bliver evalueret med både barium

kontrast røntgenundersøgelse (MBS) og fiberendoskopiske synkeundersøgelser (FEES) i løbet af

studiet. Med MBS optager man en serie af billeder ved hjælp af røntgenstråler og kontraststof, som

man enten skal drikke eller spise. Derved kan man visualisere synkeprocessen i svælget. Det samme

princip gælder ved FEES, hvor man i stedet for røntgen benytter en kikkertundersøgelse igennem


49

næsen. Desuden registreres det hvornår patienterne ikke længere har behov for en nasalsonde eller

mavesonde til ernæring, som et surrogat mål for synkefunktion.

Livskvalitet undersøges ved hjælp af tre internationalt validerede spørgeskemaer som er oversat til

dansk: EORTC QLQ-H&N35, EORT QLQ-C30 og MDADI. Toxicitet efter behandling graderes

ved brug af RTOG Late Radiation Morbidity Score skema. Endeligt udfyldes DAHANCA skemaer

i henhold til de nationale retningslinjer.

Det primære endepunkt i studiet er forskellen i synke-relateret livskvalitet (MDADI) efter 1 år.

Parametre i form af overlevelse og recidivrate (tilbagefald af kræftsygdom) bliver undersøgt i op til

5 år efter endt behandling ved brug af databasen.

Behandling af personoplysninger til forskningsprojektet vil overholde EU’s Persondataforordningen.

Der sendes en ansøgning om behandling af data til Datatilsynet. Forsøget vil derudover blive

anmeldt til den Videnskabsetiske Komite i Region Hovedstaden.

Der oprettes ingen forskningsbiobank i forbindelse med forsøget.

5. Forsøgspersoner, herunder inklusions- og eksklusionskriterier

Forsøget omfatter patienter henvist til Øre-næse-halskirurgisk og Audiologisk klinik på henholdsvis

Rigshospitalet, Odense og Aarhus Universitetshospitaler der diagnosticeres med tidligt stadie kræft

i mundsvælget. Forsøget er planlagt til at omfatte i alt 138 patienter.

Inklusionskriterier:

1. 18 år eller ældre

2. I stand til at afgive informeret samtykke

3. WHO/ECOG performance status 0-2

4. Histologisk verificeret planocellulær svælgkræft (udelukkende ganetonsil og tungerod) med

kendt p16 (proteinmarkør) status ved inklusionstidspunkt


50

5. Klinisk tumor stadie T1-2 (ifølge UICC, TNM classification, 8th edition)

6. Klinisk lymfeknude stadie N0-1 (ifølge UICC, TNM classification, 8th edition). For de p16-

positive inkluderes kun lymfeknudemetastaser der har en største diameter på 3 cm målt

billeddiagnostisk.

7. Diagnostisk billedundersøgelse (CT/MRI) udført inden for 14 dage efter

randomiseringstidspunkt

8. Operabel tumor vurderet ved MR skanning, objektiv undersøgelse og/eller

ultralydsundersøgelse.

Eksklusionskriterier:

1. Alvorlig medicinske komorbiditet (WHO performance status >2) eller andre

kontraindikationer i forhold til ståle-, kemoterapi eller kirurgi.

2. Ikke i stand til at gennemføre forløb med stråleterapi eller ambulant opfølgning.

3. Fjernmetastaser.

4. Klinisk eller radiologisk tegn på ekstrakapsulær vækst i lymfeknudemetastase.

5. Tidligere stråleterapi af hoved-hals området.

6. Tidligere hoved-hals kræft.

7. Betydelig trismus (nedsat mundåbning ≤ 35mm).

8. Manglende evne eller vilje til at udfylde livskvalitetsspørgeskemaerne.

9. Involvering af svælgets bagvæg.

10. Graviditet

6. Bivirkninger, risici og ulemper

Behandlingsarm (robotkirurgi):


51

I forbindelse med robotoperationen er der risiko for blødning, infektion, synkeproblemer inklusiv

åben snøvl, fejlsynkning, nedsat gabeevne, påvirkning af føle- og/eller smagssans svarende til

tungen, påvirkning af tungens mobilitet og aspiration med eventuel aspirations pneumoni til følge.

I forbindelse med halsdissektion er der risiko for blødning, infektion, nerveskade. Nerveskader ses i

form af:

• Ramus marginalis n. facialis (ansigtsnerven) skade, der kan give asymmetrisk mundmimik

og skævt smil.

• N. aurikularis magnus (største hudgren omkring øret) skade, hvilket kan give nedsat

følesans omkring øreflippen (papøre)

• N. accesorius (hjælpenerven) skade, hvilket kan medføre manglende evne til at løfte armen

over hovedet, muskelatrofi og skuldersmerter.

• N. hypoglossus (tungenerve) skade, hvilket kan medføre hel eller delvis lammelse af tungen,

på afficerede side.

De er risiko for kronisk faryngit (kort og på lang sigt), karakteriseret ved fornemmelse af øget

mukusdannelse i svælget.

Kontrolarm (strålebehandling med eller uden kemoterapi):

I forbindelse med strålebehandling kan der opstå ”akutte” og ”sene/kroniske” bivirkninger under

behandlingen, og er som regel forbigående og fortager sig efter behandlingen er afsluttet.

Bivirkninger der kan forekomme på kort sigt:

• Rødme, irritation og synkesmerter ved slimhinderne

• Smerter i det bestrålede område

• Mundtørhed

• Hæshed

• Svamp i mund eller svælg

• Rødme og irritation af huden

• Hævelse på halsen


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• Øget slimproduktion og hoste

• Smerter og spisebesvær

Kroniske bivirkninger/senfølger der kan forekomme:

• Tørhed i mund, svælg og hals

• Nedsat smagssans eller en oplevelse af, at maden ændrer smag

• Øget risiko for at få huller i tænderne

• Problem med at åbne munden pga. stramning i kæbeleddene

• Synke- og spisebesvær

• Hæshed

• Øget fasthed af bl.a. vævet på halsen

• Væskeansamling under hagen

• Træthed

• Nedsat produktion af skjoldbruskkirtelhormon

• Sjælden bivirkning: et lille stykke brusk i luftrør/strube eller en lille del af knoglevævet i

kæben kan løsne sig

• Meget sjælden bivirkning: at rygmarven påvirkes af strålebehandlingen, så man bl.a. får jag

af smerte ud i arme og ben

Kemobehandling i forbindelse med strålebehandling kan forværre de akutte bivirkninger af

strålebehandlingen, ligesom man kan opleve en forbigående påvirkning af følenerverne i hænder og

fødder.

Nogle oplever kvalme og eventuelt opkastninger. Da behandlingen med kemoterapeutika (cisplatin)

også kan påvirke funktionen af knoglemarven, skal man have taget blodprøver før hver ugentlig

behandling. Desuden kan man i sjældne tilfælde opleve påvirkning af evnen til at høre eller tinnitus

(øresusen) efter behandlingen.

Indberetning af alvorlige uventede hændelser:


53

Alle uønskede og alvorlige hændelser registreres i 30 dage efter endt behandling. Derudover

registreres bivirkninger efter behandlingen i op til 5 års opfølgning.

Den forsøgsansvarlige skal en gang årligt i forsøgsperioden indsende en liste til etisk komité over

alle alvorlige ventede og uventede bivirkninger samt alle alvorlige hændelser, som er indtruffet i

perioden. Indberetningen skal være ledsaget af en vurdering af forsøgspersonernes sikkerhed og

ledsages af kommentarer om eventuelle konsekvenser for forsøget..


54

7. Økonomiske forhold

Initiativtagere til forsøget er Øre-næse-halskirurgisk og Audiologisk klink på Rigshospitalet.

Følgende forsøgsansvarlige har ansvaret for behandlingen på respektive behandlingscentre:

Rigshospitalet

Øre-næse-halskirurgisk og Audiologisk Klinik: Niclas Rubek, Overlæge

Onkologisk Klinik: Jeppe Friborg, Overlæge, ph.d

Odense Universitetshospital

Øre-næse-halskirurgisk afdeling: Christian Godballe, Professor, Overlæge, ph.d.

Onkologisk Klinik: Jørgen Johansen, Overlæge, ph.d.

Aarhus Universitetshospital

Øre-næse-halskirurgisk afdeling: Thomas Kjærgaard, Overlæge, ph.d.

Onkologisk Klinik: Jesper Eriksen, Overlæge, ph.d.

Alle rekrutterende centre er økonomisk ansvarlige for alle undersøgelser og behandlingsprocedurer

som er beskrevet i protokollen. Der er ingen private støttegivere til projektet. Ingen af de

forsøgsansvarlige eller initiativtagere har nogen økonomisk tilknytning til virksomheder eller fonde

med interesser i forsøget.

Der betales ikke vederlag til forsøgspersoner som led i forsøget. Hvis behovet for yderligere ekstern

finansiering opstår, vil etisk komité blive informeret, samt blive tilføjet til den skriftlige information,

der gives til forsøgspersoner.

8. Rekruttering af forsøgspersoner

Rekruttering af forsøgspersoner der opfylder inklusionskriterierne vil foregå i alle forsøgssteder

som er danske hoved-hals kræft centre. Patienterne henvises til en øre-næse-halskirurgisk afdeling

af praktiserende læge, praktiserende øre-næse-halslæge eller af andre øre-næse-halsafdelinger i

landet. Første kontakt mellem en øre-næse-halskirurg og forsøgsperson, er i ambulatoriet på en Øre-

næse- halskirurgisk afdeling. Hvis patienten findes operabel, vil en læge fra øre-næse-halskirurgisk

afdeling og onkologisk afdeling i fælleskab vurdere, om patienten kan inkluderes i protokollen. Alle


55

samtaler foregår i en ambulatoriestue med en sygeplejerske og vil være uforstyrret. En læge vil

sørge for at give den mundtlige samt skriftlige information. Det er op til patienten, om han/hun vil

have en bisidder, og om han/hun ønsker betænkningstid (24 timer) mellem mundtlig og skriftlig

information til informeret samtykke. Hvis patienten ikke ønsker betænkningstid, vil der blive

indhentet informeret samtykke umiddelbart efter, der er givet mundtlig information, og patienten

har læst den skriftlige deltagerinformation.

Der indhentes informeret samtykke fra patienten før randomisering foretages. Samtykket giver

direkte adgang til at sponsor for forsøget, monitoreringsenhed samt relevante myndigheder kan tilgå

patientoplysninger med det formål at kontrollere og kvalitetssikre forsøget. Selve

randomiseringsprocessen foretages af sekretariatet i DAHANCA idet de besidder

randomiseringsnøglen. Dette foregår ved, at forsøgsansvarlige, eller læge på det respektive

forsøgssted sender en fax til sekretariatet efter patienten har modtaget mundtlig og skriftlig

information samt at der foreligger informeret samtykke. Dernæst modtager lægen information om

hvilken behandlingsarm patienten er randomiseret til.

Forsøgspersoner kan rekrutteres på baggrund af in- og eksklusionskriterier af alle henviste patienter,

efter de, i det rekrutterende center, har fået foretaget objektive og radiologiske undersøgelser samt

evaluering ved en multi-disiplinær team konference hvori flere lægelige specialer er repræsenteret.

Patienter, der kvalificerer sig til inklusion i studiet, vil modtage mundtlig og skriftlig information

om studiet. Alle patienter vil blive behandlet i henhold til de danske kræftpakker.

9. Offentliggørelse af forsøgsresultater

Offentliggørelse af positive, negative samt inkonklusive forsøgsresultater opnået gennem studiet

bliver offentliggjort i internationale videnskabelige tidsskrifter, på www.clinicaltrials.gov eller

www.clinicaltrialsregister.eu. Offentliggørelse af resultater foregår efter skriftlig kontrakt mellem

de primære forsøgsansvarlige og styres af sponsor-ansvarlig samt forsøgsansvarlig på

Rigshospitalet. Når alle forsøgsforløb er afsluttede og data er gjort op, vil forsøgsdeltagere have

mulighed for at blive informeret om forsøgets resultater ved at kontakte forsøgsansvarlige.

http://www.clinicaltrials.gov/


56

10. Videnskabsetisk redegørelse

Standardbehandlingen af mundsvælgkræft i Danmark er strålebehandling med eller uden

kemoterapi. I det seneste års tid har der været en stigende efterspørgsel fra patienterne med ønske

om robotkirurgisk behandling af mundsvælgkræft. Dette er hovedsageligt fordi, man ved hjælp af

robotten kan tilbyde patienterne skånsom kirurgisk behandling med en kombination af transoral

robotkirurgi og lymfeknude fjernelse på halsen som alternativ til behandling med stråle- og

kemoterapi. I et nyligt publiceret studie fra Rigshospitalet er det netop vist, at primær behandling af

mundsvælgkræft med transoral robotkirurgi er en sikker procedure der gør det muligt at opnå

kirurgisk radikalitet. Flere kliniske studier (evidensniveau II/III) har vist, at patienter med tidlige

stadier af mundsvælgkræft, der gennemgår transoral robotkirurgisk behandling som monoterapi, har

en overlevelse ligestillet med primær behandling med stråle- og kemoterapi, dog med færre

kortsigtede og langsigtede bivirkninger. Derfor forventes den ”eksperimentelle” behandling i form

af robotkirurgi som værende sikker i dette forsøg. Der er ingen publicerede randomiserede studier

der viser om den ene behandling er bedre end den anden i henhold til morbiditet med fokus på

livskvalitet. Således danner dette nationale randomiserede forsøg evidensgrundlaget for fremtidig

behandling af tidlige stadier for mundsvælgkræft.

Alle inkluderede forsøgspersoner behandles efter randomiseringsnøglen og følger de undersøgelser

der står anført i protokollen. Studiet bliver monitoreret af Good Clinical Practise (GCP enheden)

ved Aalborg og Aarhus Universitetshospitaler i henhold til protokol og aktuel lovgivning. Studiet

gennemføres i henhold til Helsinki deklarationerne.


57

References:

1. Garnaes E, Kiss K, Andersen L, Therkildsen MH, m.fl. Increasing incidence of base of

tongue cancers from 2000 to 2010 due to HPV: the largest demographic study of 210 Danish

patients. Br J Cancer 2015;113:131–4.

2. Garnaes E, Kiss K, Andersen L, Therkildsen MH, m.fl. A high and increasing HPV

prevalence in tonsillar cancers in Eastern Denmark, 2000-2010: the largest registry-based

study to date. Int J cancer 2015;136:2196–203.

3. Carlander A-LF, Grønhøj Larsen C, Jensen DH, Garnæs E, m.fl. Continuing rise in

oropharyngeal cancer in a high HPV prevalence area: A Danish population-based study from

2011 to 2014. Eur J Cancer 2017;70:75–82.

4. Garnaes E, Frederiksen K, Kiss K, Andersen L, m.fl. Double positivity for HPV DNA/p16 in

tonsillar and base of tongue cancer improves prognostication: Insights from a large

population-based study. Int J cancer 2016;139:2598–605.

5. Grønhøj Larsen C, Jensen DH, Fenger Carlander A-L, Kiss K, m.fl. Novel nomograms for

survival and progression in HPV+ and HPV- oropharyngeal cancer: a population-based study

of 1,542 consecutive patients. Oncotarget 2016;7:71761–72.

6. O’Sullivan B, Huang SH, Perez-Ordonez B, Massey C, m.fl. Outcomes of HPV-related

oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation.

Radiother Oncol Elsevier Ireland Ltd; 2012;103:49–56.

7. Attner P, Du J, Näsman A, Hammarstedt L, m.fl. Human papillomavirus and survival in

patients with base of tongue cancer. Int J Cancer 2011;128:2892–7.

8. Ang KK, Harris J, Wheeler R, Weber R, m.fl. Human papillomavirus and survival of patients

with oropharyngeal cancer. N Engl J Med 2010;363:24–35.

9. Al-Mamgani A, van Rooij P, Verduijn GM, Mehilal R, m.fl. The impact of treatment

modality and radiation technique on outcomes and toxicity of patients with locally advanced

oropharyngeal cancer. Laryngoscope 2013;123:386–93.

10. Machtay M, Moughan J, Trotti A, Garden AS, m.fl. Factors associated with severe late


58

toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An

RTOG analysis. J Clin Oncol 2008;26:3582–9.

11. Mortensen HR, Overgaard J, Jensen K, Specht L, m.fl. Factors associated with acute and late

dysphagia in the DAHANCA 6 & 7 randomized trial with accelerated radiotherapy for head

and neck cancer. Acta Oncol 2013;52:1535–42.

12. O’Sullivan B, Huang SH, Siu LL, Waldron J, m.fl. Deintensification candidate subgroups in

human papillomavirus-related oropharyngeal cancer according to minimal risk of distant

metastasis. J Clin Oncol 2013;31:543–50.

13. The Union for International Cancer Control, TNM Classification of Malignant Tumours,

Eighth edition [Internet]. [henvist 26 maj 2017].Tilgået fra: http://uicc.org/

14. Moore EJ, Hinni ML. Critical Review: Transoral Laser Microsurgery and Robotic-Assisted

Surgery for Oropharynx Cancer Including Human Papillomavirus-Related Cancer. Int J

Radiat Oncol Biol Phys Elsevier Inc; 2012;85:1163–7.

15. Hans S, Delas B, Gorphe P, Ménard M, m.fl. Transoral robotic surgery in head and neck

cancer. Eur Ann Otorhinolaryngol Head Neck Dis Elsevier Masson SAS; 2012;129:32–7.

16. Weinstein GS, O’Malley BW, Magnuson JS, Carroll WR, m.fl. Transoral robotic surgery: a

multicenter study to assess feasibility, safety, and surgical margins. Laryngoscope

2012;122:1701–7.

17. Almeida JR De, Li R, Magnuson JS, Smith R V, m.fl. Oncologic Outcomes After Transoral

Robotic Surgery A Multi-institutional Study. 2015;5820:1–9.

18. Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16+

oropharyngeal cancer. Laryngoscope 2012;122 Suppl:S13-33.

19. Dowthwaite S a, Franklin JH, Palma D a, Fung K, m.fl. The role of transoral robotic surgery

in the management of oropharyngeal cancer: a review of the literature. ISRN Oncol

2012;2012:945162.

20. Moore EJ, Olsen SM, Laborde RR, García JJ, m.fl. Long-term functional and oncologic

results of transoral robotic surgery for oropharyngeal squamous cell carcinoma. Mayo Clin


59

Proc Mayo Clin Elsevier Inc; 2012;87:219–25.

21. Kelly K, Johnson-Obaseki S, Lumingu J, Corsten M. Oncologic, functional and surgical

outcomes of primary Transoral Robotic Surgery for early squamous cell cancer of the

oropharynx: A systematic review. Oral Oncol 2014;50:696–703.

22. Weinstein GS, Quon H, Newman HJ, Chalian JA, m.fl. Transoral Robotic Surgery Alone for

Oropharyngeal Cancer. Arch Otolaryngol Head Neck Head Neck Surg 2012;138:628–34.

23. Wong LS, McMahon J, Devine J, McLellan D, m.fl. Influence of close resection margins on

local recurrence and disease-specific survival in oral and oropharyngeal carcinoma. Br J Oral

Maxillofac Surg British Association of Oral and Maxillofacial Surgeons; 2012;50:102–8.

24. Rubek N, Channir HI, Charabi BW, Lajer CB, m.fl. Primary transoral robotic surgery with

concurrent neck dissection for early stage oropharyngeal squamous cell carcinoma

implemented at a Danish head and neck cancer center: a phase II trial on feasibility and

tumour margin status. Eur Arch Otorhinolaryngol 2017;274:2229–37.

25. Sinha P, Piccirillo JF, Kallogjeri D, Spitznagel EL, m.fl. The role of postoperative

chemoradiation for oropharynx carcinoma: A critical appraisal of the published literature and

National Comprehensive Cancer Network guidelines. Cancer 2015;121:1747–54.

26. Amini A, Jasem J, Jones BL, Robin TP, m.fl. Predictors of overall survival in human

papillomavirus-associated oropharyngeal cancer using the National Cancer Data Base. Oral

Oncol 2016;56:1–7.

27. Lewis JS, Carpenter DH, Thorstad WL, Zhang Q, m.fl. Extracapsular extension is a poor

predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma.

Mod Pathol 2011;24:1413–20.

28. Sinha P, Kallogjeri D, Gay H, Thorstad WL, m.fl. High metastatic node number, not

extracapsular spread or N-classification is a node-related prognosticator in transorally-

resected, neck-dissected p16-positive oropharynx cancer. Oral Oncol 2015;51:514–20.

29. Sinha P, Lewis JS, Piccirillo JF, Kallogjeri D, m.fl. Extracapsular spread and adjuvant

therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer


60

2012;118:3519–30.

30. Huang SH, Hansen A, Rathod S, OʼSullivan B. Primary surgery versus (chemo)radiotherapy

in oropharyngeal cancer. Curr Opin Otolaryngol Head Neck Surg 2015;23:139–47.

31. Lim YC, Koo BS, Lee JS, Lim J-Y, m.fl. Distributions of cervical lymph node metastases in

oropharyngeal carcinoma: therapeutic implications for the N0 neck. Laryngoscope

2006;116:1148–52.

32. Van Abel KM, Moore EJ. Focus issue: neck dissection for oropharyngeal squamous cell

carcinoma. ISRN Surg 2012;2012:547017.

33. Norling R, Therkildsen MH, Bradley PJ, Nielsen MB, m.fl. Nodal yield in selective neck

dissection. 2013;April:965–71.

34. Weinstein GS, Quon H, Newman HJ, Chalian JA, m.fl. Transoral robotic surgery alone for

oropharyngeal cancer: an analysis of local control. Arch Otolaryngol Head Neck Surg

2012;138:628–34.

35. Grant DG, Hinni ML, Salassa JR, Perry WC, m.fl. Oropharyngeal cancer: a case for single

modality treatment with transoral laser microsurgery. Arch Otolaryngol Head Neck Surg

2009;135:1225–30.

36. Shin HA, Lim YC, Jeong HM, Choi EC. Role of primary surgery for early-stage (T1-2N0)

squamous cell carcinoma of the oropharynx. Oral Oncol Elsevier Ltd; 2009;45:1063–6.

37. Choby GW, Kim J, Ling DC, Abberbock S, m.fl. Transoral robotic surgery alone for

oropharyngeal cancer: quality-of-life outcomes. JAMA Otolaryngol Head Neck Surg

2015;141:499–504.

38. Dziegielewski PT, Teknos TN, Durmus K, Old M, m.fl. Transoral robotic surgery for

oropharyngeal cancer: long-term quality of life and functional outcomes. JAMA Otolaryngol

Head Neck Surg 2013;139:1099–108.

39. Hutcheson KA, Holsinger FC, Kupferman ME, Lewin JS. Functional outcomes after TORS

for oropharyngeal cancer: a systematic review. Eur Arch Oto-Rhino-Laryngology

2015;272:463–71.


61

40. Dawe N, Patterson J, O’Hara J. Functional swallowing outcomes following treatment for

oropharyngeal carcinoma: a systematic review of the evidence comparing trans-oral surgery

versus non-surgical management. Clin Otolaryngol 2016;41:371–85.

41. Chen AM, Daly ME, Luu Q, Donald PJ, m.fl. Comparison of functional outcomes and

quality of life between transoral surgery and definitive chemoradiotherapy for oropharyngeal

cancer. Head Neck John Wiley and Sons Inc; 2015;37:381–5.

42. Rosenthal DI, Mendoza TR, Ph D, Fuller CD, m.fl. Prospective Analysis Using the MD

Anderson Symptom. 2015;120:1975–84.

43. Hajdú SF, Plaschke CC, Johansen C, Dalton SO, m.fl. Cross-Cultural Translation,

Adaptation and Reliability of the Danish M. D. Andeson Dysphagia Inventory (MDADI) in

Patients with Head and Neck Cancer. Dysphagia 2017;32:472–9.

44. Hutcheson KA, Barrow MP, Lisec A, Barringer DA, m.fl. What is a clinically relevant

difference in MDADI scores between groups of head and neck cancer patients?

Laryngoscope 2016;126:1108–13.

45. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group

(RTOG) and the European organization for research and treatment of cancer (EORTC). Int J

Radiat Oncol 1995;31:1341–6.

46. Dijkstra PU, Huisman PM, Roodenburg JLN. Criteria for trismus in head and neck oncology.

Int J Oral Maxillofac Surg 2006;35:337–42.

47. Sundhedsstyrelsen (kræftpakkeforløb) [Internet]. [henvist 27 februar 2017].Tilgået fra:

https://www.sst.dk/da/sygdom-og-behandling/kraeft/pakkeforloeb

48. Retningslinjer for strålebehandling i DAHANCA. 2013;0–30.

49. Channir HI, Rubek N, Nielsen HU et al. Transoral robotic surgery for the management of

head and neck squamous cell carcinoma of unknown primary. Acta Otolaryngol

2015;135:1051–7.

50. El-Naggar AK, Chan JKC, Grandis JR, Takata T, m.fl. Pathology and Genetics of Head and

Neck Tumours / World Health Organization Classification of Tumours. 2017.


62

51. Saund DSS, Pearson D, Dietrich T. Reliability and validity of self-assessment of mouth

opening: a validation study. BMC Oral Health 2012;12:48.

52. Danish Head and Neck Cancer Group (https://www.dahanca.oncology.dk/).

53. Zhang X, Loberiza FR, Klein JP, Zhang M-J. A SAS macro for estimation of direct adjusted

survival curves based on a stratified Cox regression model. Comput Methods Programs

Biomed 2007;88:95–101.

54. More YI, Tsue TT, Girod D a, Harbison J, m.fl. Functional swallowing outcomes following

transoral robotic surgery vs primary chemoradiotherapy in patients with advanced-stage

oropharynx and supraglottis cancers. JAMA Otolaryngol Head Neck Surg 2013;139:43–8.


63

Addendum

Figure 1: Study design


64

Table 1: The 8th edition of UICC clinical tumour and nodal stages (cT and cN) of p16-positive and

p16-negative OPSCC.

p16-postive OPSCC

p16-negative OPSCC

Clinical tumour stage

cT1: Tumour 2 cm or less in greatest

dimension

Tumour 2 cm or less in greatest

dimension

cT2: Tumour more than 2 cm but not

more than 4 cm

Tumour more than 2 cm but not more

than 4 cm

cT3: Tumour more than 4 cm in greatest

dimension, or extension to lingual

surface of epiglottis

Tumour more than 4 cm in greatest

dimension, or extension to lingual

surface of epiglottis

cT4: Tumour invades any of the

following: larynx, deep/ extrinsic

muscle of tongue (genioglossus,

hyoglossus, palatoglossus, and

styloglossus), medial pterygoid,

hard palate, mandible*, lateral

pterygoid muscle, pterygoid plates,

lateral nasopharynx, skull base; or

encases carotid artery

cT4a: Tumour invades any of the

following: larynx*, deep/ extrinsic

muscle of tongue (genioglossus,

hyoglossus, palatoglossus, and

styloglossus), medial pterygoid, hard

palate, mandible

cT4b: Tumour invades any of the


65

following: lateral pterygoid muscle,

pterygoid plates, lateral nasopharynx,

skull base; or encases carotid artery

Clinical nodal stage

cN0: No regional lymph node metastasis No regional lymph node metastasis

cN1: Unilateral metastasis, in lymph

node(s), all 6 cm or less

Metastasis in a single ipsilateral

lymph node, 3 cm or less in greatest

dimension without extranodal

extension


66

cN2: Contralateral or bilateral metastasis

in lymph node(s), all 6 cm or less in

greatest dimension

cN2a: Metastasis in a single

ipsilateral lymph node more than 3 cm

but not more than 6 cm in greatest


extension.

cN2b: Metastasis in multiple lymph

nodes, none more than 6 cm in

greatest dimension, without

extranodal extension.

cN2c: Metastasis in bilateral or

contralateral lymph nodes, none more

than 6 cm in greatest dimension,

without extranodal extension.

cN3: Metastasis in lymph node(s) greater

than 6 cm in dimension

cN3a: Metastasis in a lymph node

more than 6 cm in greatest dimension


cN3b: Metastasis in a lymph node


with extranodal extension**.

OPSCC: Oropharyngeal squamous cell carcinoma

*Mucosal extension to lingual surface of epiglottis from primary tumours of the base of tongue and vallecular does not

constitute invasion of the larynx.

**The presence of skin involvement or soft tissue invasion with deep fixation tethering to underlying muscle or

adjacent structures or clinical signs of nerve involvement is classified as clinical extranodal extension.


67

Note: Midline nodes for both p16-positive and p16-negative OPSCC are considered ipsilateral nodes.

Table 2: The 8th edition of UICC pathologic nodal stages (pN) of p16-positive and p16-negative

OPSCC.

p16-postive OPSCC

p16-negative OPSCC

Pathologic nodal stage

pN0: No regional lymph node metastasis No regional lymph node metastasis

pN1: Metastasis in 1 to 4 lymph node(s) Metastasis in a single ipsilateral

lymph node, 3 cm or less in greatest


extension


68

pN2: Metastasis in 5 or more lymph

node(s)

pN2a: Metastasis in a single

ipsilateral lymph node, less than 3 cm

in greatest dimension with

extranodal extension or more than

3cm but not more than 6 cm in

greatest dimension without extranodal

extension.

pN2b: Metastasis in multiple

ipsilateral lymph nodes, none more


without extranodal extension

pN2c: Metastasis in bilateral or

contralateral lymph nodes, none more


without extranodal extension

pN3: - pN3a: Metastasis in a lymph node



pN3b: Metastasis in a lymph node


with extranodal extension or, multiple

ipsilateral, or any contralateral or

bilateral node(s) with extranodal


69

extension.

Table 2: The definition of new primary cancer vs. local recurrence

OROPHARYNGEAL SQUAMOUS CELL CARCINOMA

Recurrence New Primary cancer

T-POSITION • Distance to ”new” cancer ≤ 5

cm

• And time duration from

tumour origin ≤ 5 år

• And same histology

• Distance to new cancer > 5 cm

• Or time duration > 5 år

• Or different histology

N-POSITION • No new primary tumour

• And same histology

(time span is not a factor)

• New primary tumour most likely

source

• Or different histology (in case of

biopsy)


M-POSITION • No new primary tumour

• And same histology (in case of

biopsy)


• New primary tumour more likely

source

• Or different histology


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