Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation
Phase: PHASE2
Conditions: Adenoid Cystic Carcinoma
Sponsor: Heidelberg University

 
 
 
 
 
 
Klinik  für  RadioOnkologie  und  Strahlentherapie  
- Czerny-Klinik  - 
am Universitätsklinikum
 Heidelberg  
 
 
 
 
study protocol ACCO-Studie 
version 1.3 from 01.10.2018 
 
 
 
 
 
 
Study protocol 
 
Adenoid cystic Carcinoma and Carbon ion Only irradiation  
 
ACCO-study  
 
 
- prospective, open, randomized, two-armed, phase II study - 
 
 
 
 
Version 1.3(engl); 01.10.2018 
 
 
 
 
 
Principal Investigator 
Prof. Dr. Klaus Herfarth 
University Hospital Heidelberg 
Dept. of Radiation Oncology (Czerny-Klinik) 
Im Neuenheimer Feld 400 
69120 Heidelberg 
Germany 
 
 
 
 
 
 
The contents of the protocol are to be treated confidentially and may not be passed on orally or in 
writing to non-participants without the approval of the study management. 
 
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Institution : 
Dept. of Radiation Oncology 
Chair: Prof. Dr. Dr. Jürgen Debus 
University of Heidelberg 
Im Neuenheimer Feld 400, 69120 Heidelberg 
phone: +49-6221-56 8201 
fax: +49-6221-56 5353 
juergen.debus@med.uni-heidelberg.de 
 
Principal Investigator:
 
Prof. Dr. Klaus Herfarth 
Vice chair Dept. of Radiation Oncology 
University of Heidelberg 
Im Neuenheimer Feld 400, 69120 Heidelberg 
phone: +49-6221-56 8202 
fax: +49-6221-56 5353 
klaus.herfarth@med.uni-heidelberg.de 
 
Study  Coordinator:  
Dr. Sebastian Adeberg 
Dept. of Radiation Oncology 
University of Heidelberg 
Im Neuenheimer Feld 400, 69120 Heidelberg 
phone: +49-6221-56 8202 
fax: +49-6221-56 5353 
sebastian.adeberg@med.uni-heidelberg.de 
 
Study  Statistician : 
Prof. Dr. Meinhard Kieser 
Chair Institute for Medical Biometry and Informatics 
University of Heidelberg 
Im Neuenheimer Feld 130.3, 69120 Heidelberg 
phone: +49-6221-56 4140 
fax: +49-6221-56 4195 
meinhard.kieser@imbi.uni-heidelberg.de 
 
Study Nurse : 
Karen Lossner 
Dept. of Radiation Oncology 
University of Heidelberg 
Im Neuenheimer Feld 400, 69120 Heidelberg 
phone.: +49-6221-56 37748 
fax: +46-6221-56 1979 
karen.lossner@med.uni-heidelberg.de 
 
 
 
 
 
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Data Safety Monitoring Board : 
Prof. Dr. Marc Münter 
Katharinenhospital  
Kriegsbergstr. 60 
70174 Stuttgart 
phone: +49-711-278 34201 
fax: +49-711-278 34209 
m.muenter@klinikum-stuttgart.de 
 
Prof. Dr. Florian Sterzing 
Strahlentherapie Süd 
Am Klinikum Kempten 
Robert-Weixler-Straße 50 
87439 Kempten 
phone.: +49-831-960 7940 
fax: +49-831-960 7943456 
f.sterzing@strahlentherapie-kempten.de 
 
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Index 
1.0 Synopsis  .................................................................................................................................. 7 
2.0 Summary  ............................................................................................................................... 11 
3.0 Background  ........................................................................................................................... 11 
3.1 Radiotherapy with photons .................................................................................................. 11 
3.2 Radiotherapy with neutrons ................................................................................................. 11 
3.3 Radiotherapy with combined modality (IMRT + C12) ........................................................... 12 
3.4 Radiotherapy with carbon ions ............................................................................................ 12 
4.0 Study objectives  ................................................................................................................... 13 
4.1 Primary Objective ................................................................................................................ 13 
4.2 Secondary Objective ........................................................................................................... 13 
5.0 Study Design  ......................................................................................................................... 13 
6.0 Participating investigators/study centers
 ........................................................................... 14 
7.0 Selection of Patients  ............................................................................................................. 14 
7.1 Inclusion Criteria ................................................................................................................. 14 
7.2 Exclusion Criteria ................................................................................................................ 14 
8.0 Patient registration  ............................................................................................................... 15 
9.0 Treatment planning  ............................................................................................................... 15 
9.1 Radiation therapy ................................................................................................................ 15 
9.2 Treatment planning ............................................................................................................. 15 
9.3 Contouring .......................................................................................................................... 15 
9.4 Dose prescription ................................................................................................................ 16 
9.5 Organs at risk ...................................................................................................................... 17 
9.6 Controls at the irradiation device ......................................................................................... 18 
9.7 Supportive measures during radiation therapy .................................................................... 18 
10.0 Clinical examinations (visits)
 ............................................................................................. 18 
10.1 Overview ........................................................................................................................... 18 
10.2 Initial examination ............................................................................................................. 19 
10.3 Final examination .............................................................................................................. 19 
10.4 Follow up ........................................................................................................................... 19 
11.0 Duration of study participation
 .......................................................................................... 19 
11.1 Premature withdrawal of patients from the study ............................................................... 19 
12.0 Assessment of efficacy
 ...................................................................................................... 20 
12.1 Timeline  ............................................................................................................................... 20 
12.2 Definition of relapse........................................................................................................... 20 
13.0 Safety  ................................................................................................................................... 20 
13.1 Assessment of Safety ........................................................................................................ 20 
13.2 Data Safety Monitoring Board ........................................................................................... 20 
14.0 Duration of  the study/study withdrawal
 ............................................................................ 21 
4.1 Regular end of study  ............................................................................................................ 21 
14.2 Premature end of tria l/ Withdrawal of the whole study ...................................................... 21 
14.3 Individual criteria for withdrawal ........................................................................................ 21 
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15.0 Biometrics  ........................................................................................................................... 21 
15.1 Sample size calculation ..................................................................................................... 21 
15.2 Randomization .................................................................................................................. 21 
15.3 Study Population ............................................................................................................... 22 
15.2 Evaluation ......................................................................................................................... 22 
16.0 Data management  ............................................................................................................... 23 
16.1 Patient identification log .................................................................................................... 23 
16.2 Data collection/ Case Report Forms .................................................................................. 23 
16.3 Archiving of Essential Documents ..................................................................................... 23 
16.4 Data protection .................................................................................................................. 23 
17.0 Ethical Aspects  ................................................................................................................... 23 
17.1 Declaration of Helsinki ....................................................................................................... 23 
17.2 Ethics Committee .............................................................................................................. 24 
17.3 Subject information and informed consent ......................................................................... 24 
17.4 Informed consent for irradiation ......................................................................................... 24 
17.5 Usage, storage and circulation of data .............................................................................. 24 
18.0 Legal and administrative aspects
 ...................................................................................... 24 
18.1 GCP .................................................................................................................................. 24 
18.2 Legal aspects .................................................................................................................... 24 
18.3 Radiation protection and insurance ................................................................................... 25 
18.4 Funding ............................................................................................................................. 25 
18.5 Publication ........................................................................................................................ 25 
18.6 Adherence to protocol and protocol amendments ............................................................. 25 
19.0 Literature  ............................................................................................................................. 26 
20.0 Signature Page  .................................................................................................................... 28 
 
 
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0.0 Abbreviations  
Abbreviation 
ACC 
Adenoid cystic carcinomas  
ALARA 
As low as reasonable achievable 
BED 
Biologically Effective Dose 
BfS 
Bundesamt für Strahlenschutz (Federal Office for 
Radiation Protection) 
C12 ion 
carbon ions 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
clinical target volume 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FU 
follow up 
Fx 
fractionation 
GTV 
Gross tumor volume 
HIMAC 
Heavy-Ion Medical Accelerator  
HIT 
Heidelberg Ion Beam Therapy Center  
IMRT 
intensity-modulated radiotherapy 
KI 
Karnofsky performance index 
LC 
local control 
LEM 
Local Effect Model 
LET 
linear energy transfer  
MIT 
Marburg Ion Beam Therapy Center 
MRI 
Magnetic Resonance Imaging 
PI 
principal investigator 
QLQ-C30  
Quality of life questionnaires - general 
QLQ-H&N35  Quality of life questionnaires - head and neck 
RBE 
Relative biological effectiveness 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SOBP 
spreadout Bragg peak  
TD 
Total dose 
tox 
toxicity 
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1.0 Synopsis  
ACCO-study synopsis 
Titel 
Adenoid cystic Carcinoma and Carbon ion Only irradiation 
Acronym 
ACCO  
Prinicipal Investigator 
Prof. Dr. Klaus Herfarth 
Dept. of Radiation Oncology 
University of Heidelberg 
Study Coordinator 
Dr. Sebastian Adeberg 
Dept. of Radiation Oncology 
University of Heidelberg 
Study Statistician 
Prof. Dr. Meinhard Kieser 
Institute for Medical Biometry and Informatics 
University of Heidelberg 
Study Phase/Type 
Prospective open phase II / Investigator-Initiated study 
Planned Start of Study 
Q4 2018 
End of Study 
Last patient in: Q4/2025 
Last patient out: Q4/2030 
Study Objectives 
Loco-regional control rate after 5 years 
Design of Study 
Monocentric open, prospective, randomized two-armed phase II 
study 
Planned Patient Number 
314 patients 
Inclusion Criteria 
 
Histologically confirmed adenoid cystic carcinoma in the 
head and neck area 
 
Indication for irradiation: 
o non-operable and/or 
o R1 / R2 resected and/or 
o Perineural sheath invasion (Pn +) and/or 
o pT3 / pT4 
 
Informed consent 
 
KI > 60% or ECOG 0/1 (minimum: self-sufficiency, normal 
activity or work not possible) 
 
Age 18-80 years 
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ACCO-study synopsis 
Exclusion Criteria 
 
Rejection of study participation by the patient 
 
Patient is not able to consent 
 
Stage IV (distant metastases), with exception of pulmonary 
metastases of ≤ 1 cm 
 
Lymph node involvement (clinical or pathological) 
 
Previous radiotherapy in the head and neck area 
 
Active medical implants for which there is no authorization 
for ion irradiation at the time of treatment (e.g., cardiac 
pacemaker, defibrillator, ...) 
 
Contraindication to MR imaging 
 
Simultaneous participation in another clinical study that 
could influence the outcome of this study or the other study 
Description of Therapy 
Loco-regional radiotherapy with carbon ions (C12) (experimental 
arm) versus photon IMRT + C12-Boost (control arm) 
Definition of Target 
Volume 
Primary tumor region with clinical safety margin considering the 
perineural spreading path 
Organs at Risk 
Brainstem, spinal cord, inner ear, temporal poles, optic chiasm, 
optic nerves on both sides, eyeball, lens, lacrimal gland, 
temporomandibular joints, Gll. parotis, Gll. submandibularis 
Planned Study Duration 
per Patient 
Irradiation planning: 2 weeks 
Duration of irradiation:  
~4 weeks (22 fractions) experimental arm 
~6 weeks (33 fractions) control arm 
Follow-up: 60 months from start of irradiation 
Conduct of Study 
Ion beam therapy centers of the University Hospital Heidelberg in 
Marburg or Heidelberg. The treatment is carried out on an 
outpatient basis. 
Checkliste before Start of 
Therapy 
 
Informed consent for study participation 
 
Current MR imaging incl. T1 / T2 Fat-Sat images (not older 
than 2 months) 
 
CT Chest (not older than 3 months) 
 
CT / sonography liver (not older than 3 months) 
 
Bone scintigraphy 
 
medical history and medical findings (weight, height, 
Karnofsky performance index) 
 
Quality of life questionnaires QLQ-C30 and QLQ-H&N35  
 
Tooth reconstruction and fabrication of a fluoridation splint 
for irradiations in the jaw area 
 
randomization 
Examinations during 
Radiotherapy 
Documentation of clinical symptoms and toxicities (according to 
the NCI CTCAE version 4.0 criteria) 
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ACCO-study synopsis 
Follow-up Examinations 
6 weeks after the end of irradiation, then 6 months after the start of 
treatment and further every 6 months in the first two years, 
annually in the 3rd to 5th year 
Follow-up includes clinical findings, MRI, toxicity and quality of life, 
CT chest (once a year starting from follow-up month 12) 
Primary Objective Criteria Local-regional control rate after 5 years 
Secondary Objective 
Criteria 
Progression-free survival (5 years) 
Overall survival (5 years) 
Acute toxicity (CTC AE V4.0) 
Late toxicity (CTC AE V4.0) 
Quality of life (QLQ-C30 and QLQ-H&N35) 
Study Population 
The ITT population includes all randomized patients who are 
evaluated in the treatment arm to which they have been 
randomized. The ITT population is the primary scoring collective 
for all efficacy endpoints and patient characteristics. 
Per-protocol population (PP): All patients in the ITT population 
who have received the planned therapy in full and whose 
documentation is at least as complete as possible to derive 
conclusions about efficacy from the data. Analyzes of PP 
populations serve as sensitivity analyzes to investigate the 
robustness of the results from the ITT population. 
Safety population: All patients in the ITT population who have 
started the planned therapy (at least 1 day). Patients in the safety 
population are evaluated in the treatment arm they have been 
treated for. This is the primary evaluation collective for all safety 
endpoints. 
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ACCO-study synopsis 
Biometrical Methods 
The primary objective of the study is to demonstrate that the local 
control rate 5 years after locoregional radiotherapy with C12 ions 
π_C12 is greater than the local control rate of bimodal 
radiotherapy π_bim. The null hypothesis (H0: π_C12≤π_bim; "the 
local control rate 5 years after locoregional radiotherapy with C12 
ions is less than or equal to the local control rate in bimodal 
radiotherapy") is tested at the unilateral level α = 0.15, for the 
alternative of a local control rate 5 years after locoregional 
radiotherapy with C12 ions of π_C12 = 70% and in bimodal 
radiotherapy of π_bim = 60% (power of 0.75). For this purpose, a 
case number of 266 patients (133 per arm) is necessary using a 
Chi² test. Assuming a drop-out rate of 15%, 314 patients will be 
included in the study. 
 
The primary endpoint "locoregional tumor control according to MRI 
imaging after 5 years" is evaluated by means of a logistic 
regression model which is adjusted for the factors "residual tumor 
present" (yes / no) and "lung metastases present" (yes / no). In 
addition, the associated odds ratio for the treatment effect is given 
with a two-sided 70% confidence interval, missing values of the 
primary endpoint are replaced by multiple imputation, and the 
minor outcome criteria are evaluated using descriptive data 
analysis methods. In addition to specifying appropriate summary 
measures of the empirical distribution, descriptive two-sided 95% 
confidence intervals are given. 
End of Study 
The study ends with the follow-up visit at month 60 after inclusion 
of the last patient. 
 
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2.0 Summary  
Adenoid cystic tumors are rare tumors of the head and neck region. Despite their slow growth, re-
irradiation is often necessary due to the high metastatic risk. Patients are usually irradiated with 
photons or, as here at the Heidelberg University Hospital, with a combination of carbon ions and 
photons (bimodal radiotherapy). So far, there is no data from Europe available for the sole 
irradiation with carbon ions. The present ACCO (Adenoid Cystic Carcinoma and Carbon ion Only 
irradiation) study, a prospective, open-label, phase II, two-armed, randomized, investigator-initiated 
study, will therefore investigate the sole radiotherapy of carbon ions compared to bimodal 
radiotherapy in this tumor entity. Irradiation is applied in about 4 weeks (22 fractions); in a 
significantly shorter interval than the combination therapy (6 weeks, 33 fractions). Patients are 
followed up for further 5 years after the start of therapy. Carbon ions alone are expected to 
increase local tumor control rates from 60% to 70% after 5 years (primary objective criterion of this 
study). In order to reject the null hypothesis with a power of 75% and a one-sided significance level 
of α=15%, 314 patients are included (including a drop-out rate of 15%). Secondary objective 
criteria are progression-free survival, overall survival, acute and late toxicity, and quality of life. 
 
3.0 Background  
Adenoid cystic carcinomas are rare tumors (incidence 0.14 - 0.64 / 100,000), which occur mostly in 
the head and neck region (large and small salivary glands, nasal mucosa) and account for about 
10-15% of malignant salivary gland tumors. They grow slowly; however, due to their growth pattern 
exhibit a tendency for local recurrences. For this reason postoperative irradiation is indicated, 
especially in the presence of risk factors (pT3 / 4, R1 / 2, Pn1). Lymphocytic metastasis is detected 
in 19% of salivary gland ACCs (GROUP 2017). The lymphocytic metastasis rate in ACCs of the 
nasopharynx, paranasal sinuses, lacrimal glands, or external auditory canal is only 5% (GROUP 
2016). The most common hematogenous metastasis occurs in the lungs with an incidence of 35-
50% (Bradley 2004). Other sites of metastasis are liver and bone. Patients with lung metastases 
can live asymptomatic for a relatively long time with the local control of the primary tumor being 
crucial for quality of life; while overall survival of patients with bone and liver metastases decreases 
significantly (median 54 months to median 20 months; (Sung, Kim et al. 2003)). 
3.1 Radiotherapy with photons
 
Due to the rarity of ACC, reports of these tumors are usually retrospective analyses by individual 
clinics or institutes, extending over a very long period of time with changing radiation technology. 
Our own experience using modern photon techniques with a median dose of 66 Gy (single dose 
1.8 - 2 Gy) resulted in a local control rate of 56% after 3 years and 40% after 5 years in 37 patients 
(Jensen, Nikoghosyan et al. 2015). 30% of the patients had an acute grade 3 toxicity of the 
mucosae. Higher-grade late radiation effects were reported in only 3% (hearing impairment) 
(Jensen, Nikoghosyan et al. 2015). Mendenhall and colleagues reported a local control rate of 77% 
after 5 years. However, in primary-irradiated (non-operated) patients, the control rate dropped to 
56% (Mendenhall, Morris et al. 2004). 
3.2 Radiotherapy with neutrons
 
Neutrons belong to the ion beams with a high linear energy transfer (high-LET). For a long time, 
adenoid cystic carcinomas were considered as the prime example for neutron irradiation as they 
resulted in the best control rates. In a South African series of 108 patients with ACC and 
macroscopic (residual) tumor, the 5-year local control was 52% (Stannard, Vernimmen et al. 
2013). At dkfz, 29 patients with macroscopic ACC were treated with neutrons. The 5-year local 
control rate was 75%. The main problem of neutron irradiation are the late complications. In an 
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analysis of 335 neutron-treated salivary gland tumors, the actuarial risk of grade 3 or grade 4 
complications was 20% (Stannard, Vernimmen et al. 2013). 17% of dkfz patients also exhibited 
late grade 3/4 toxicities. 
3.3 Radiotherap y with combined modality 
(IMRT + C12) 
Since 1997, our clinic collected data on combined irradiation with IMRT photons including the first 
draining lymph node area and a carbon ion boost of 6-8 fractions with 3 Gy (RBE) single doses. 
Initial data on this combined modality was published by Schulz-Ertner et. al. in 2005 and showed 
an advantage compared to the department's historical IMRT technique alone (Schulz-Ertner, 
Nikoghosyan et al. 2005). In 2015, this data was updated by Jensen et al. and extended with all 
patients who had received ion boost irradiation from the Gesellschaft für Schwerionenforschung 
(GSI) Darmstadt by the year 2007 (Jensen, Nikoghosyan et al. 2015): The 58 patients (all with 
macroscopic (residual) tumor) who received a combined therapy showed a progression free 
survival of 84% at 3 years and 60% after 5 years, at a median follow-up time of 74 months. This 
was significantly better than the historical comparison of 37 patients treated with a single IMRT 
(median follow-up 63 months, local PFS 3 years 59%, 5 years 40%). This benefit is also reflected 
in a significant survival benefit: median overall survival in the combination treatment is 102 months 
versus 74 months after IMRT alone (p = 0.015) (Jensen, Nikoghosyan et al. 2015). The COSMIC 
trial examined this methodology in a prospective fashion enrolling 53 patients with malignant 
salivary gland tumors (Jensen, Nikoghosyan et al. 2010). ACC histology was present in 47 patients 
(89%) and 33 patients (62%) had macroscopic (residual) tumor. With a median follow-up of 42 
months, the local progression-free survival of ACC patients was 82% at 3 years, thus confirming 
the retrospective data from the previously mentioned GSI collective (Jensen, Nikoghosyan et al., 
2015). 
The toxicity of this combination treatment was not a limiting factor: In the COSMIC trial, reported 
severe grade 3 toxicities (> grade 2) were grade 3 mucositis in 25% of patients and grade 3 
dermatitis in 10% of patients (Jensen, Nikoghosyan et al. 2015). In one patient, a higher grade late 
complication occurred (a carotid hemorrhage). In the GSI collective, late complications were a 
unilateral hearing loss in 10% of patients, a loss of smelling in 10% of patients and a unilateral 
blindness due to retinal detachment in one patient (2%) (Jensen, Nikoghosyan et al. 2015). 
Due to the results of the GSI collective and the COSMIC study, bimodal therapy can be regarded 
as standard therapy. 
3.4 Radiotherapy with carbon ions
 
Data for the sole treatment with carbon ions of ACC are from Japan. All treatments were done with 
passive beam modulation. To calculate the biological dose, dose profiles were performed 
assuming a fixed spreadout Bragg peak (SOBP). This system differs from GSI's local effect model 
(LEM) for C12 irradiation with active scanning. Conversion tables are used to compare the 
biological calculated doses (RBEHIMAC vs. RBELEM) (Steinstrater, Grun et al., 2012). In addition, the 
irradiation in Japan was carried out with 3-4 fractions per week. 
Mizoe et al. published data on dose escalation in a group of salivary gland tumors, of which 68% 
had ACC histology (Mizoe, Tsujii et al., 2004). The dose was increased from 18 x 2.7 Gy 
(RBEHIMAC) to 18 x 3.9 Gy (RBEHIMAC) with 3 exposures per week. In a later group, this was 
increased to 16 fractions (4x / week) with 3.3 - 4.0 Gy (RBEHIMAC). The local control rates of these 
two groups did not differ significantly, reaching 75% at 3 years, 65% at 4 years and 60% at 5 
years. Acute toxicities > grade 2 on the mucous membranes was described in only one patient 
(3%). No patient developed a late toxicity > grade 2. 
In a later series of 113 ACC patients, 16 fractions of 3.7 - 4.0 Gy (RBEHIMAC) were administered 
(Ikawa, Koto et al.). Here, 3, 4, 5-year local control rates of 89%, 82% and 69% were achieved. 37 
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patients (33%) exhibited acute grade 3 toxicities of the mucous membranes. Late radiation effects 
≥ grade 3 were reported in 27 patients (24%) (grade 3: cataract (10), osteoradionecrosis (7), brain 
necrosis (2), glaucoma (2), vision deterioration (2), mucosal ulcer (2); grade 4: Brain necrosis (3), 
blindness (5)). 
Table: Japanese ACC studies with sole C12 irradiation: 
Author 
n 
Single 
dose (SD) 
[Gy(RBEHIM
AC)] 
Fx 
Total dose 
[Gy(RBEHIM
AC)] 
Correspond
s SD [Gy 
(RBELEM)] 
BED 
2 
Gy 
(α/β=3.5) 
5 yrs 
LC 
[%] 
Late 
tox ≥3 
Ikawa 
(Ikawa, 
Koto 
et 
al.) 
113 
3.7-4.0 
16 
57.6 – 64.0 
4.2 – 4.4 
92 - 101 
69% 
24% 
Mizoe 
(Mizoe, 
Tsujii et 
al. 2004) 
17 
2.7 – 3.9 
18 
48.6 – 70.2 
3.0 – 3.9 
64 - 94 
75% 
0% 
Mizoe 
(Mizoe, 
Tsujii et 
al. 2004) 
19 
3.3 – 4.0 
16 
52.8 – 64.0 
3.7 – 4.4 
87 - 101 
50% 
0% 
The University Hospital of Heidelberg has gained experience with sole C12 ions irradiation in the 
recurrence situation after previous irradiation (Jensen, Poulakis et al. 2015): 52 patients previously 
irradiated with a median dose of 66 Gy (20 -115 Gy) were re-irradiated using carbon ions. The 
median dose was 51 Gy (RBE) in 17 fractions. Third-degree cerebral radiation necrosis occurred in 
2 patients (4%), a third-degree dysphagia in 1 patient (2%), and 2 patients suffered grade 4 carotid 
haemorrhages at a median follow-up of 14 months. The rate of serious late complications was 
6.5%. In particular, carotid haemorrhages are most likely due to the very high cumulative dose of 
the previous and current radiation (150 Gy and 180 Gy). The local tumor control was - pursuant to 
the lower radiation dose in the re-irradiation situation - at only 70% after 1 year (Jensen, Poulakis 
et al. 2015). 
 
4.0 Study  objectives  
4.1 Primary Objective  
 Loco-regional tumor control according to MR imaging after 5 years 
4.2 Secondary Objective  
 Progression-free survival after 3 and 5 years 
 Overall survival after 3 and 5 years 
 Acute toxicities according to NCI CTC AE (Version 4.0) during and up to 6 weeks after 
radiotherapy (rate of toxicity > 2 grade) 
 Late toxicities according to NCI CTC AE (Version 4.0) from 6 weeks after radiotherapy (rate of 
toxicity > 2 grade) 
 
5.0 Study  Design  
Prospective, open, two-armed, randomized, phase II study 
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6.0 Participating investigators/
study centers  
The study performed as a monocentric study. The center for this study is: 
 
 
Department of Radiation Oncology and Radiotherapy 
 
Chair: Prof. Dr. Dr. Jürgen Debus 
 
University Hospital Heidelberg 
 
Im Neuenheimer Feld 400, 69120 Heidelberg, Germany 
 
phone: +49-6221-568201 
 
fax: +49-6221-565353 
 
The center has two locations, the Heidelberg Ion Beam Therapy Center (HIT) and the Marburg Ion 
Beam Therapy Center (MIT). Patients will be recruited and treated at both locations. 
Head of the clinical study for radiotherapy is Prof. Dr. med. Klaus Herfarth, Department of 
Radiation Oncology and Radiotherapy, University of Heidelberg. 
The study coordination is carried out by Dr. med. Sebastian Adeberg, Department of Radiation 
Oncology and Radiotherapy, University of Heidelberg. 
Additional physicians are the physicians at the Heidelberg Ion Beam Therapy Center (HIT) and 
Marburg Ion Beam Therapy Center (MIT) at the Department of Radiation Oncology and 
Radiotherapy at the University of Heidelberg. 
Biometric planning is carried out by Prof. Dr. med. Meinhard Kieser, Institute of Medical Biometry 
and Informatics, University of Heidelberg. 
 
7.0 Selection of Patients  
7.1 Inclusion Crite ria 
 Histologically confirmed adenoid cystic carcinoma in the head and neck area 
 Indication for irradiation: 
    non-operable and/or 
    R1/R2 resected and/or 
    perineural sheat invasion (Pn+) and/or 
    pT3/pT4 
 Informed consent 
 KI > 60% or ECOG 0/1 (minimum: self-sufficiency, normal activity or work not possible) 
 Age 18-80 years 
 
7.2 Exclusion Criteria  
 rejection of the study by the patient 
 Patient is not able to consent 
 Stage IV (distant metastases) 
 lymph node involvement (clinical or pathological), with exception of pulmonary metastases of 
≤ 1 cm 
 Previous radiotherapy in the head and neck area 
 Active medical implants for which there is no ion radiation authorization at the time of 
treatment (e.g., cardiac pacemaker, defibrillator, ...) 
 Contraindication to MR imaging 
 Simultaneous participation in another clinical study that could influence the outcome of this 
study or the other study 
 
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8.0 Patient registration  
The study center keeps a logbook in which all patients who meet the selection criteria are recorded 
consecutively and documented in a registration form. If not included in the study, the reason is 
documented. All patients who fulfill the selection criteria, who have been informed and have given 
their consent to participate in the study, are registered as recruited at the study center and will be 
randomized subsequently. For this purpose, the registration form and the signed informed consent 
are handed over or faxed to the study center. In the study center, the registration form is checked 
for completeness and the patient is recorded in the logbook. 
The informed consent of each patient takes place through a conversation between the study 
physician and the patient before inclusion in the study. The physician has to give the patient 
sufficient time for reflection and opportunity for further inquiries and must be convinced that the 
informed consent was understood by the patient. All questions of the patient must be answered 
and any ambiguities eliminated. The consent of the patient must explicitly refer to the collection 
and processing of personal data. Therefore, patients are explicitly informed about the purpose and 
scope of the survey and the use of this data, in particular health data. The storage of full names, 
dates of birth, addresses, and telephone numbers in the study center will be recorded in writing. 
The patient may withdraw consent at any time and without giving any reason and discontinue the 
study. In such a case, he should be asked to give the reason for the termination, but pointed out 
that he does not have to do this. 
 
9.0 Treatment planning  
 
Screening of the patient, indication 
 
Informed consent of the patient 
 
Randomization 
 
Acquisition of the medical history and medical findings (Karnofsky performance index, 
height, weight) 
 
Quality of life assessment (QLQ-C30 and QLQ-H&N35) 
 
Current MR imaging incl. T1 / T2 Fat-Sat images (not older than 2 months) 
 
CT Chest (not older than 3 months) 
 
CT / sonography liver (not older than 3 months) 
 
Bone scintigraphy 
 
Tooth reconstruction and fabrication of a fluoridation splint for irradiation in the jaw area 
 
9.1 Radiation therapy  
Radiation therapy is performed at the Heidelberg Ion Beam Therapy Center and at the Marburg Ion 
Beam Therapy Center using carbon ions alone (experimental arm) or using bimodal radiotherapy 
(control arm). In the experimental arm, a total of 22 fractions are administered in about 4 weeks (5-
6 fractions per week). This corresponds to a significant reduction of the treatment time compared 
to the standard arm (33 fractions in about 6 weeks). The relative biologically effective dose is 
calculated from the physical dose using LEM1 and an alpha/beta value of 2. 
 
9.2 Treatment planning  
The patient is immobilized by the use of a thermoplastic mask. Computed tomography must be 
performed without contrast enhancement in 3 mm layers and if possible also with contrast medium. 
 
9.3 Cont ouri ng 
The following structures should be contoured: 
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Targets  experimental arm : 
 
GTV 
Macroscopic tumor extension according to MRI at the time of treatment 
planning 
 
GTVinit  
initial GTV: preoperative tumor in operated patients 
 
CTV_BP 
GTV and possibly GTVinit plus 6 mm margin (9 mm along the perineural 
spreading path), considering anatomical boundaries 
 
CTV_GP 
CTV_BP plus 6 mm margin (12 mm along the perineural spreading path), 
considering anatomical boundaries; thereby partially included lymph node 
stations should be included completely 
 
Targets  control arm : 
 
GTV 
Macroscopic tumor extension according to MRI at the time of treatment 
planning 
 
GTVinit  
initial GTV: preoperative tumor in operated patients 
 
CTV_BP 
GTV and possibly GTVinit plus 6 mm margin (9 mm along the perineural 
spreading path), considering anatomical boundaries 
 
CTV_GP 
CTV_BP plus 3 mm margin and draining lymph nodes (level II and III only), 
in case of crossing the mid line, bilateral 
 
 
Risk structures : 
 
 
brainstem 
 
spinal cord 
 
inner ear 
 
temporal pole 
 
chiasma opticum 
 
optic nerve on both sides 
 
eyeball 
 
lens 
 
lacrimal gland 
 
temporomandibular joints 
 
Gll. parotis 
 
Gll. Submandibularis 
 
9.4 Dose prescription  
The aim of optimizing the treatment plan is to achieve an as homogeneous and conformal dose 
distribution and maximum protection of the organs at risk as possible. The maximum exposure of 
the organs at risk should not exceed the TD 5/5 (toxic dose that causes 5% serious complications 
in 5 years) of the respective organs. The protection of spinal cord, chiasm and brain stem is a high 
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priority. The preservation of the respective optic nerves should be accomplished according to the 
initial tumor spread in consultation with the patient. 
 
Table 1: The dosages refer to 95% of the volume. For carbon ions, the biological dose is based on 
the local effect model (LEM) 1, taking into account an alpha/beta value of 2 for all tissues. 
 
 
Experimental arm  
C12-only RT  
Control arm  
Bimodal RT (p hoton s&C12) 
 
CTV_GP 
CTV_BP 
CTV_GP 
CTV_BP 
Single dose 
3 Gy(RBE) 
3 Gy(RBE) 
2 Gy 
3 Gy(RBE) 
Total dose 
51 Gy(RBE) 
15 Gy(RBE) 
50 Gy 
24 Gy (RBE) 
BED2Gy* 
61 Gy 
18 Gy 
50 Gy 
29 Gy 
* The equivalent dose BED2Gy is the dose corresponding to the applied dose in conventional 
fractionation (i.e., 2 Gy single dose, calculated with an α/β = 3 Gy for ACC). 
 
9.5 Organs at risk  
When complying with the tolerance doses, the fractionation effect must be taken into account in 
case of different partial exposure in the basic plan and boost plan. Here, the reference dose of 2 
Gy and an α/β = 2 Gy applies to the organs at risk. 
Table 2: Tolerance doses for organs at risk. 
 
TD / Isodose 
experimental arm 
BED2Gy* 
Comment  
Brain stem 
54 Gy(RBE) / 82% 
60 Gy 
Maximum surface 
Optic chiasma 
49.5 Gy(RBE) / 75% 
52.6 Gy 
Maximum 
Optic nerves** 
49.5 Gy(RBE) / 75% 
52.6 Gy 
Maximum 
Spinal cord 
45 Gy(RBE) / 68% 
45.3 Gy 
Maximum 
Parotid gland**** 
31 Gy(RBE) / 47% 
26.4 
Mean Dose 
Mandible bone 
60 Gy(RBE) / 90% 
69.8 Gy 
Maximum surface 
Lens*** 
ALARA 
 
 
Bulb*** 
ALARA 
 
 
Lacrimal gland*** 
ALARA 
 
 
Inner ear*** 
ALARA 
 
 
Temporomanibular 
joint*** 
ALARA 
 
 
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* The values listed here also apply to the bimodal therapy, using an alpha / beta of 3 for the 
respective risk organs. 
** Higher doses possible, after documented consultation with the patient that he accepts blindness 
of the respective side for achieving higher tumor control probability. 
*** ALARA = As low as reasonable achievable 
**** if not part of the target volume (e.g. contralateral side) 
9.6 Controls at the irradiation device
 
The correct patient position during C12 irradiation is checked by means of daily orthogonal X-ray 
imaging and corrected if necessary. The irradiation in the control arm is performed as IMRT with 
image control, whereby the frequency of the image control can be determined individually 
depending on positioning inaccuracy and adjacent risk structure. 
9.7 Supportive measures during radiation therapy
 
Radiation therapy is performed under outpatient conditions, inpatient admission for supportive 
therapy is possible at all times. 
For target volumes with dose administration in the oral region or of the oro- or hypopharynx, 
supportive therapy with oral rinsing, Amphomoronal and Glandosane is recommended. 
 
10.0 Clinical examinations (visits)
 
10.1 Overview  
Clinical visits and content correspond to those of standard therapy. Study-related additional (time) 
effort results from the regular completion of the quality of life questionnaires (about 15 minutes per 
visit). 
 
 
IE 
FE 
FU week 6 
FU month 6 
FU month 12 
FU month 18 
FU month 24 
FU month 36 
FU month 48 
FU month 60 
In-/exclusion criteria fulfilled 
x 
Informed consent 
x 
Medical history/findings 
xa 
x 
x 
x 
x 
x 
x 
x 
x 
Karnofsky performance index 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
Weight  
x 
x 
x 
x 
x 
x 
x 
x 
x 
QLQ-C30 and QLQ-H&N35  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Symptomes/Toxicities CTC AE 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Documentation staging examin. 
xb 
MRI 
xc 
xe 
xe 
xe 
xe 
xe 
xe 
xe 
xe 
CT chest 
xd 
x 
x 
x 
x 
x 
CT/Sonography Liver 
xd 
Bone scintigraphy 
x 
Scheduling FU  
 
x 
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IE: Initial examination; FE: final examination of RT; FU: follow up; a incl. report and histology of 
surgery; b staging examination of chest, liver, bone; MRI head/neck; c less than 2 months old; d 
less than 3 months old; e including documentation of the remission status (remission, stable 
disease, progress) 
 
10.2 Initial examination  
 Medical history (incl. report and histology of surgery) 
 Documentation of staging examination (chest, liver, bones, MRI head/neck) 
 Assessment of quality of life (EORTC QLQ-C30 and QLQ-H&N35) 
 Assessment of symptoms according to NCI CTC AE (version 4.0) criteria  
 
10.3 Final examination  
On the last day of irradiation (+/- 1 day) the final examination takes place with the investigator:  
 Evaluation and documentation of toxicity  
 Quality of life assessment using EORTC QLQ-C30 and QLQ-H&N35  
 Scheduling of further follow-up appointments 
 
10.4 Follow  up 
The oncological follow-up begins 6 weeks after the end of radiotherapy. Further follow-up 
appointments take place after 6, 12, 18, 24, 36, 48 and 60 months. 
The following parameters are documented: 
 
Clinical status incl. Karnofsky performance index, weight 
 
Documentation of toxicities according to CTC AE 4.0 
 
MRI head/neck with remission status (remission, stable disease, progress) 
 
Quality of life assessment using EORTC QLQ-C30 and QLQ-H&N35 
 
CT chest (annually) 
 
11.0 Duration of study p articipation  
Patients are recruited over a period of 7 years. The evaluation of the study results regarding the 
primary endpoint of the study (locoregional control), takes place 60 months after the start of 
irradiation of the last patient. The end of the study is defined as the end of the follow-up period of 
the last patient (60 months after the start of treatment). 
The planned start of the study is the fourth quarter of 2018. 
 
first patient in 
last patient in 
last patient out 
Q4/2018 
Q4/2025 
Q2/2030 
 
11.1 Premature  withdrawal  of patients from the study  
Individual termination criteria during the treatment phase: 
 
at any time at the request of the patient 
 
occurrence of therapy-resistant severe side effects (CTC grade 4 toxicity, which does not 
recover spontaneously, after supportive therapy or after a radiation break) 
 
Individual termination criteria during the follow-up phase: 
 
at any time at the request of the patient 
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 
tumor recurrence 
 
Further procedures after termination: 
In addition to the radiotherapeutic care for the documentation of late toxicities; toxicities are also 
recorded after completion of the study-related follow-up phase in cooperation with the supervising 
head and neck surgeon (only with the consent of the patient). 
 
12.0 Assessment of efficacy
 
12.1 Timeline  
Submission of the complete protocol for review in the Ethics Committee and the Bundesamt für 
Strahlenschutz is scheduled for the first quarter of 2018. Recruitment start is scheduled for the 
fourth quarter of 2018. With a recruitment of about 45 patients per year, the fourth quarter of 2025 
is aimed for as end of the recruitment. 
 
12.2 Definition of relapse  
A direct implementation of the RECIST criteria on the Response Evaluation is often not possible 
due to the growth behavior of the frequently occurring radiogenic changes in the irradiated area. 
The response evaluation is therefore primarily descriptive. A recurrence suspicion should be 
validated in a second examination 2-3 months later. 
 
13.0 Safety  
13.1 Assessment of Safety  
The acute and late toxicities of radiotherapy are based on the NCI CTCAE Version 4.0 criteria and 
are recorded during and after therapy continuously at the respective follow-up appointments. 
 
Grade 1 = mild (no therapeutic measures required) 
Grade 2 = moderate (outpatient drug therapy) 
Grade 3 = difficult (inpatient therapy) 
Grade 4 = life-threatening or leading to disabilities 
Grade 5 = side effect with lethal consequences 
 
Typical toxicities and their classifications according to CTC AE V4 are listed in the appendix of the 
protocol. 
 
13.2 Data Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will monitor recruitment, reported 
adverse events and data quality at least once a year. Based on its report, the DSMB will make 
recommendations to the principal investigator regarding the modification, continuation or 
termination of the study. The DSMB consists of independent experts in the field of radiation 
oncology (Prof. Dr. Marc Münter, Klinikum Stuttgart and Prof. Dr. Florian Sterzing, Strahlentherapie 
Süd, Kempten). The mission of the DSMB will be to ensure the ethical conduct of the study, as well 
as the protection of safety interests of the patients in the study. Problems that are identified will be 
discussed with the PI who will take appropriate action. Relevant information (including relevant 
safety data) is included in the status reports of the study, which serves as a base of discussion for 
the study team sessions in which the PI, the study coordinator and sub-investigators participate. 
 
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14.0 Duration of the study /study  withdrawal  
4.1 Regul ar end of study  
Regular end of the treatment phase: 4 weeks after the start of radiotherapy (C12 irradiation only); 6 
weeks after the start of radiotherapy (bimodal radiotherapy) 
Regular end of study participation: after a follow-up period of 5 years 
 
14.2 Premature end of tria  l/ Withdrawal of the whole 
study  
Reasons for premature termination of the entire study are: 
 
Decision including benefit-risk assessments of the study management when unacceptable 
risks and toxicities occur 
 
Consideration of termination for each grade 5 toxicity, 2 consecutive grade 4 toxicities, 5 
consecutive grade 3 toxicities 
 
new (scientific) evidence during the study 
 
Inadequate recruitment rate 
 
14.3 Individual criteria for withdrawal
 
 serious event during the radiation phase (grade 4 or 5 toxicity) 
 Withdrawal of the patient's consent to study participation 
 
15.0 Biometri cs 
15.1 Sample size calculation  
The primary objective of the study is to demonstrate that the local control rate 5 years after 
locoregional radiotherapy with C12 ions π_C12 is greater than the local control rate of bimodal 
radiotherapy π_bim. Control rates of approximately 60% were observed with treatment with IMRT 
and C12 Boost and it is estimated that this rate could be improved by 10% under C12 (see chapter 
3.4). The null hypothesis (H0: π_C12≤π_bim; "the local control rate after 5 years in locoregional 
radiotherapy with C12 ions is less than or equal to the local control rate in bimodal radiotherapy") is 
tested at the unilateral level α = 0.15, for the alternative of a local control rate 5 years after 
locoregional radiotherapy with C12 ions of π_C12 = 70% and in bimodal radiotherapy of π_bim = 
60% (power of 0.75). For this purpose, a number of 266 patients (133 per arm) is necessary using 
a Chi² test. Assuming a drop-out rate of 15%, 314 patients will be included in the study. Evaluation 
by means of a logistic regression model, which is adjusted for the factors "residual tumor present" 
and "lung metastases present", an increased power is expected due to the additionally explained 
variance. Missing values are to be replaced by multiple imputation (see Section 15.4), which is 
also to be expected to increase power. The calculations were done with nQuery Advisor version 
7.0. 
 
15.2 Randomization  
Successively screened and eligible patients will be included in the study after study start. To obtain 
comparable treatment groups (experimental group: locoregional radiotherapy with C12 ions, 
control group: bimodal radiotherapy) with respect to known ("residual tumor presence" (yes / no) 
and "lung metastases present" (yes / no)) and unknown risk factors, each patient becomes 
randomized to the treatment groups in balanced permutated blocks and stratified for residual tumor 
and lung metastases using the web-based software randomizer.at (by the Institute of Medical 
Informatics, 
Statistics 
and 
Documentation 
of 
the 
Medical 
University 
of 
Graz 
(https://www.randomizer.at) provided). 314 patients will be randomized. 
 
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15.3 Study Population  
The ITT population includes all randomized patients who are evaluated in the treatment arm to 
which they have been randomized. The ITT population is the primary scoring collective for all 
efficacy endpoints and patient characteristics. 
Per-protocol population (PP): All patients in the ITT population who have received the planned 
therapy in full and whose documentation is at least as complete as possible to derive conclusions 
about efficacy from the data. Analyzes of PP populations serve as sensitivity analyzes to 
investigate the robustness of the results from the ITT population. 
Safety population: All patients in the ITT population who have started the planned therapy (at least 
1 day). Patients in the safety population are evaluated in the treatment arm they have been treated 
for. This is the primary evaluation collective for all safety endpoints. 
 
The assignment of each patient to the different analysis populations (ITT, PP, safety population) is 
defined and explained in detail in the statistical analysis plan. 
 
15.2 Evaluation  
The primary endpoint "locoregional tumor control according to MRI imaging after 5 years" is 
evaluated by means of a logistic regression model which is adjusted for the factors "residual tumor 
present" (yes / no) and "lung metastases present" (yes / no). The null hyposthesis is tested to the 
one-sided level of α = 0.15. The increased significance level compared to a confirmatory Phase II 
study on the one hand takes into account the phase II character of the study and, on the other 
hand, the number of patients that can be recruited in a manageable time frame with which a 
sufficiently high level of power can be achieved. In addition, the corresponding odds ratio for the 
treatment effect is given with a two-sided 70% confidence interval: Missing values of the primary 
endpoint are replaced by multiple imputation, using the "fully conditional specification" Method (van 
Buuren, 2007). The factors "treatment group" (experimental arm / control arm), "residual tumor 
present "(yes / no) and" lung metastases present "(yes / no)" will be accounted for in the imputation 
process. Sensitivity analyzes include a complete case analysis as well as a best and worst case 
analysis. In addition, the time-to-event curve for the main objective criterion is estimated using the 
Kaplan and Meier method (1958). 
 
The study is supervised by an independent Data Safety Monitoring Board (DSMB), which 
assesses the benefit-risk profile of the studied therapy during the course of the study and, if 
necessary, informs the study management, if the DSMB considers changes to the study execution 
as necessary. The corresponding assessment and, if applicable, a resulting recommendation of 
the DSMB will be delivered to the principal investigator. 
 
The secondary objective criteria are evaluated by methods of descriptive data analysis (Abt, 1987). 
Corresponding to the scaling level, suitable positional and scattered measures of the empirical 
distribution are specified for ordinal and interval-scaled variables. For nominally scaled endpoints, 
absolute and relative frequencies are calculated. For time-to-event endpoints, the Kaplan-Meier 
method estimates the probability of each target event occurring as a function of time. In addition, 
descriptive interpretive two-sided 95% confidence intervals - for time-to-event endpoints with 
adequate consideration of censored observations – will be calculated and reported. Further details 
of the evaluation are specified in a statistical analysis plan, which will be finalized before the 
database is closed. All calculations are done with SAS version 9.4 or higher. 
 
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16.0 Data management  
16.1 Patient identification log
 
All patient-related data are recorded in a pseudonymised form. Each patient is uniquely identified 
by a patient identification number. The investigator maintains a patient identification list in which 
the patient identification numbers are associated with the full patient name. This list must be kept 
absolutely confidential and must not leave the testing center. The patient identification list must be 
archived for at least 15 years after the end of the study. 
 
16.2 Data collection/ Case Report Forms
 
Data collection is based on case report forms. The sheets have to be filled in with a ballpoint pen. 
Entries in pencil or ink are not allowed. Corrections are to be carried out in the following way: The 
incorrect entry is crossed out with a simple line, the correct information is entered next to it and 
initialed by the investigator with the date and, if necessary, provided with the reason for the 
correction. Data fields which cannot be completed due to missing information must be commented 
on. 
The CRFs should be completed without delay and then should be checked by the investigator, 
signed with the date and sent to the study center. 
 
16.3 Archiving of Essential Documents
 
The originals of all crucial study documents, including CRFs, are kept in the study center for at 
least 15 years after the final report has been prepared. 
The principal investigator of the study center keeps the administrative documents (correspondence 
with the ethics committee, study administration, study center), the patient identification list, the 
signed declarations of consent, copies of the CRFs and the general study documentation (protocol, 
amendments) for the above mentioned time. 
Original data of the patients (medical records) must be kept for the required archiving period of the 
study center, but not less than 15 years. 
 
16.4 Data protection  
Personal data (full name, date of birth, address) and data on the treatment and the course of the 
disease (medical findings, types of treatment, prescribed medication, etc.) from the study 
participants will be collected. These data are subject to medical confidentiality and the provisions 
of the Bundesdatenschutzgesetzes (BDSG). They are electronically stored and evaluated in a 
pseudonymised* form using an unique identification number. Patient data will only be shared in a 
pseudonymised form. Third parties do not get any insight into original documents. 
* Pseudonym means that only a number or letter code is used, possibly in combination with initials 
and the year of birth (not date of birth). A subsequent assignment of the samples / data to a 
specific person is only possible with the help of a "key" code, which is managed in the study 
center. 
 
17.0 Ethical Aspects  
17.1 Declaration of  Helsinki  
The study will be carried out in accordance with the ethical principles described in the applicable 
version of the Declaration of Helsinki. 
 
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17.2 Ethi cs Committee  
The study protocol, patient information and the informed consent document are submitted to the 
ethics committee of the Medical Faculty of the University of Heidelberg. The study will begin only 
after receiving the approval vote. The Ethics Committee will be promptly informed by the principal 
investigator of any changes in the study protocol that may affect patient safety. 
 
17.3 Subject information and informed consent
 
Before being admitted to the clinical study, the patient must consent to participate after being fully 
informed by the investigator or a designated member of the investigating team about the nature, 
importance, risks and individual consequences of the clinical study and their right, to terminate the 
participation at any time. The informed consent to participate in the clinical study may be 
withdrawn by the patient verbally in the presence of, or in written form directed to, the investigator 
or a physician member of the investigating team at any time during the study. The patient must not 
entail any disadvantage or be coerced or unduly influenced to continue to participate. Furthermore, 
the patient is not obligated to disclose reasons for the withdrawal of the consent. 
 
After reading the informed consent document, the patient must give consent in writing. The patient 
should also have the opportunity to consult the investigator, or a physician member of the 
investigating team about the details of the clinical study. The patient's consent must be confirmed 
by the personally dated signature of the patient and by the personally dated signature of the 
physician conducting the informed consent discussion. 
 
17.4 Informed consent  for irradiation  
All patients will receive a separate information about the radiation procedure and will give their 
informed consent to irradiation. This information will specify the risks of the procedure according to 
the treatment site. The informed consent for the irradiation will be documented on the site specific 
head and neck forms and archived along with the radiation plan and radiation protocol. 
 
17.5 Usage, s torage and circulation
 of data  
The rules on medical confidentiality and data protection will be respected. Patients are informed 
that their disease-related data are stored in pseudonymised form and used for scientific 
evaluations (publications, registration dossiers). Patients have the right to be informed about the 
stored data. An inspection of the original medical records by a third party is only carried out by the 
principal investigator or officials of competent supervisory authorities. Data managers are required 
to maintain strict confidentiality and privacy. 
Upon withdrawal from the study, data already collected will be destroyed if the patient has not 
consented to further use of the data. 
 
18.0 Legal and administrative aspects
 
18.1 GCP 
This study complies with the recommendations of Good Clinical Practice (refer to ICH-GCP: 
International Conference on Harmonisation - Good Clinical Practice; 01.05.1996)  
 
18.2 Legal aspects  
The statutory requirements of the Radiation Protection Ordinance (Strahlenschutzverordnung, 
Bundesgesetzblatt 2001 Part I No. 38, dated 26.07.2001, last amended by Article 5 paragraph 7 of 
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the Law of 24.02.2012), the X-ray Ordinance (Röntgenverordnung) and the Directive on Radiation 
Protection (Richtlinie zum Strahlenschutz) are complied with. 
The principal investigator has at least two years of experience in clinical trials. 
 
18.3 Radiation protection and insurance
 
The study was reported to the Federal Office for Radiation Protection (Bundesamt für 
Strahlenschutz; BfS). The BfS confirmed application of radiotherapy in the experimental arm on the 
24.09.2018. The BfS will be informed about the amendment of the 24.09.2018, which includes 
randomization against a control arm.  A radiation protection insurance will be completed for the 
patients (insurer: HDI-Gerling Industrie Versicherung AG, insurance number 57 010310 03018). 
Study-related radiation exposure will only be initiated once the required approvals have been 
obtained from the BfS. The permit requirement is based on the use of carbon ions. All radiological 
examinations for staging during the follow-up phase correspond to clinical routine. 
 
18.4 Funding  
The Radiology Department, Department of Radiology and Radiation Therapy, University Hospital 
Heidelberg, INF 400, 69120 Heidelberg, will cover the costs of the clinical study. The study will be 
submitted to the Deutsche Krebshilfe for funding. Personnel resources for the treating physicians, 
study nurses, the data management and project management are applied for. In addition, printing 
costs, travel expenses (for the DSMB and the exchange HIT / MIT), monitoring, the fees of the 
ethics committee and the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz), 
as well as for the patient insurance are requested. Participation in the study will not cause any 
additional costs for patients (compared to the standard treatment). All persons involved (including 
the principal investigator and coordinator) declare that there is no conflict of interest in connection 
with the implementation and evaluation of the study. 
 
18.5 Public ation  
The results of the study will be published. The order of authorship is determined by the principal 
investigator. 
 
18.6 Adherence  to protocol and protocol 
amendments  
The study protocol must be adhered to. Any deviation from the intended examination and 
treatment measures or dates for which the investigator or a physician member of the investigating 
team is responsible must be documented and justified (for example, emergency measures). 
Amendments or addendums to the study protocol can only be initiated and authorized by the 
principal investigator. 
 
 
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19.0 Literature  
Abt, K. (1987). Descriptive data analysis: a concept between confirmatory and exploratory data 
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Bradley, P. J. (2004). "Adenoid cystic carcinoma of the head and neck: a review." Curr Opin 
Otolaryngol Head Neck Surg 12(2): 127-132. 
INTERNATIONAL HEAD AND NECK SCIENTIFIC GROUP (2016). "Cervical lymph node 
metastasis in adenoid cystic carcinoma of the sinonasal tract, nasopharynx, lacrimal glands and 
external auditory canal: a collective international review." J Laryngol Otol 130(12): 1093-1097. 
INTERNATIONAL HEAD AND NECK SCIENTIFIC GROUP (2017). "Cervical lymph node 
metastasis in adenoid cystic carcinoma of the major salivary glands." J Laryngol Otol 131(2): 96-
105. 
Ikawa, H., M. Koto, R. Takagi, D. K. Ebner, A. Hasegawa, K. Naganawa, T. Takenouchi, T. Nagao, 
T. Nomura, T. Shibahara, H. Tsuji and T. Kamada "Prognostic factors of adenoid cystic carcinoma 
of the head and neck in carbon-ion radiotherapy: The impact of histological subtypes." 
Radiotherapy and Oncology 123(3): 387-393. 
Jensen, A. D., A. Nikoghosyan, C. Windemuth-Kieselbach, J. Debus and M. W. Munter (2010). 
"Combined treatment of malignant salivary gland tumours with intensity-modulated radiation 
therapy (IMRT) and carbon ions: COSMIC." BMC Cancer 10: 546. 
Jensen, A. D., A. V. Nikoghosyan, K. Lossner, T. Haberer, O. Jakel, M. W. Munter and J. Debus 
(2015). "COSMIC: A Regimen of Intensity Modulated Radiation Therapy Plus Dose-Escalated, 
Raster-Scanned Carbon Ion Boost for Malignant Salivary Gland Tumors: Results of the 
Prospective Phase 2 Trial." Int J Radiat Oncol Biol Phys 93(1): 37-46. 
Jensen, A. D., A. V. Nikoghosyan, M. Poulakis, A. Hoss, T. Haberer, O. Jakel, M. W. Munter, D. 
Schulz-Ertner, P. E. Huber and J. Debus (2015). "Combined intensity-modulated radiotherapy plus 
raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck 
results in superior locoregional control and overall survival." Cancer 121(17): 3001-3009. 
Jensen, A. D., M. Poulakis, A. V. Nikoghosyan, N. Chaudhri, M. Uhl, M. W. Munter, K. K. Herfarth 
and J. Debus (2015). "Re-irradiation of adenoid cystic carcinoma: analysis and evaluation of 
outcome in 52 consecutive patients treated with raster-scanned carbon ion therapy." Radiother 
Oncol 114(2): 182-188. 
Kaplan E.L., Meier P (1958). Nonparametric estimation from incomplete observations. JASA, 53: 
457–481.  
Mendenhall, W. M., C. G. Morris, R. J. Amdur, J. W. Werning, R. W. Hinerman and D. B. Villaret 
(2004). "Radiotherapy alone or combined with surgery for adenoid cystic carcinoma of the head 
and neck." Head Neck 26: 154 – 162. 
 
Mizoe, J. E., H. Tsujii, T. Kamada, Y. Matsuoka, H. Tsuji, Y. Osaka, A. Hasegawa, N. Yamamoto, 
S. Ebihara and A. Konno (2004). "Dose escalation study of carbon ion radiotherapy for locally 
advanced head-and-neck cancer." Int J Radiat Oncol Biol Phys 60(2): 358-364. 
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Schulz-Ertner, D., A. Nikoghosyan, B. Didinger, M. Munter, O. Jakel, C. P. Karger and J. Debus 
(2005). "Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation 
therapy techniques." Cancer 104(2): 338-344. 
Stannard, C., F. Vernimmen, H. Carrara, D. Jones, S. Fredericks, J. Hille and E. de Kock (2013). 
"Malignant salivary gland tumours: Can fast neutron therapy results point the way to carbon ion 
therapy?" Radiotherapy and Oncology 109(2): 262-268. 
Steinstrater, O., R. Grun, U. Scholz, T. Friedrich, M. Durante and M. Scholz (2012). "Mapping of 
RBE-weighted doses between HIMAC- and LEM-Based treatment planning systems for carbon ion 
therapy." Int J Radiat Oncol Biol Phys 84(3): 854-860. 
Sung, M. W., K. H. Kim, J. W. Kim, Y. G. Min, W. J. Seong, J. L. Roh, S. J. Lee, T. K. Kwon and S. 
W. Park (2003). "Clinicopathologic predictors and impact of distant metastasis from adenoid cystic 
carcinoma of the head and neck." Arch Otolaryngol Head Neck Surg 129(11): 1193-1197Van 
Buuren, S. (2007). “Multiple imputation of discrete and continuous data by fully conditional 
specification.” Statistical methods in medical research 16(3): 219-242. 
 
 
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20.0 Signature Page  
 
 
 
________________________________ 
Prof. Dr. Klaus Herfarth 
Principal Investigator 
 
 
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