Quality of Life After primary TORS vs IMRT The QoLATI ... 34.pdf · Katalin Kiss, MD3 Claus Jensen,...
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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
Email: [email protected]
**Principal investigator is the responsible leader of the investigator team
Investigator***, Oncology Department, Rigshospitalet and Herlev Hospital
Jeppe Friborg, MD, PhD2
Email: [email protected]
***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
Email: [email protected]
Investigator***, Department of Oncology, Næstved Sygehus
Mohammad Farhadi, MD
Email: [email protected]
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Investigator***, Department of Otorhinolaryngology - Head & Neck Surgery, Odense
University Hospital
Christian Godballe, Professor, MD, PhD
Email: [email protected]
Investigator***, Department of Oncology, Odense University Hospital
Jørgen Johansen, MD, PhD
Email: [email protected]
***Investigator role is the responsible person for conducting the protocol at each department.
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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
Email: [email protected]
Investigator***, Department of Oncology, Aarhus University Hospital
Jesper Eriksen, MD, PhD
Email: [email protected]
***Investigator role is the responsible person for conducting the protocol at each department.
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.
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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.
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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.
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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.
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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.
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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
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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
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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)
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• 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.
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The definition of local, regional or distant recurrences versus new primary, is defined Table 2,
Addendum.
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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.
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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
• Toxicity: RTOG Late Radiation Morbidity Score
• Clinical assessment of T- and N-site, registration of secondary parameters and adverse
events
12 months ±14 days
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• QoL questionnaires (EORTC QLQ-H&N35, EORTC QLQ-C30 and MDADI)
• Toxicity: RTOG Late Radiation Morbidity Score
• 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.
• Clinical assessment of T- and N-site, registration of secondary parameters and adverse
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.
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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
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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.
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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.
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The primary contact person is Birgitte Horst Andreasen.
Contact details:
GCP-enheden ved Aalborg og Aarhus Universitetshospitaler
Olof Palmes Allé 15
8200 Aarhus N
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.
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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.
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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.
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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
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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.
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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)
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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.
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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.
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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.
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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.
Email: [email protected]
Forsøgsansvarlig på Øre-næse-halskirurgisk og Audiologisk Klinik, Rigshospitalet,
Blegdamsvej 9, 2100 København Ø
Koordinator for alle forsøgsansvarlige
Niclas Rubek, Overlæge
Email: [email protected]
Forsøgsansvarlig på Onkologisk Klinik, Rigshospitalet
Jeppe Friborg, Overlæge, ph.d.
Email: [email protected]
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Forsøgsansvarlig på Onkologisk afdeling, Herlev Hospital
Jens Bentzen, Overlæge
Email: [email protected]
Forsøgsansvarlig på Onkologisk afdeling, Næstved Sygehus
Mohammad Farhadi, Overlæge
Email: [email protected]
Forsøgsansvarlige på Øre-næse-halskirurgisk afdeling F, Odense Universitetshospital, Søndre
Blvd. 29, 5000 Odense C
Christian Godballe, Professor, Overlæge, ph.d.
Email: [email protected]
Forsøgsansvarlige på Onkologisk afdeling, Odense Universitetshospital, Søndre Blvd. 29, 5000
Odense C
Jørgen Johansen, Overlæge
Email: [email protected]
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.
Email: [email protected]
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
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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
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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):
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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:
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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..
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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
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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.
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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.
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Addendum
Figure 1: Study design
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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
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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
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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
dimension without extranodal
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
without extranodal extension.
cN3b: Metastasis in a lymph node
more than 6 cm in greatest dimension
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.
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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
dimension without extranodal
extension
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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
than 6 cm in greatest dimension,
without extranodal extension
pN2c: Metastasis in bilateral or
contralateral lymph nodes, none more
than 6 cm in greatest dimension,
without extranodal extension
pN3: - pN3a: Metastasis in a lymph node
more than 6 cm in greatest dimension
without extranodal extension.
pN3b: Metastasis in a lymph node
more than 3 cm in greatest dimension
with extranodal extension or, multiple
ipsilateral, or any contralateral or
bilateral node(s) with extranodal
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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)
(time span is not a factor)
M-POSITION • No new primary tumour
• And same histology (in case of
biopsy)
(time span is not a factor)
• New primary tumour more likely
source
• Or different histology
(time span is not a factor)