De-Intensification Radiotherapy Postoperative Head Neck
De-Intensification Radiotherapy Postoperative Head Neck
In patients with squamous cell carcinoma of the oral cavity, the oropharynx and larynx with
 >= pT3 and or pN+ postoperative radio - or radiochemotherapy is the standard of care.
 Postoperative radiochemotherapy is indicated in patients with multiple lymph node metastasis,
 lymph node metastasis with extracapsular spread and or R1/2 resection.

 Locoregional control rates are over 80% after surgery and radio(chemo)therapy. But many
 patients suffer from therapy-related long-term side-effects, like xerostomia, dysphagia,
 fibrosis, trismus etc.

 The aim of this study is to investigate if depending on primary tumor stage, quality of
 resection ( resection margin) and number of lymph node metastasis and performed neck
 dissection an adapted de-intensified dose- and target volume concept may be performed without
 reducing locoregional-control but with reducing radiotherapy-related side-effects.
The study is a non-randomized phase-II trial. In total there are 3 therapy arms.

 Patients are assigned to one of these therapy arms according to the tumor status and the
 quality and kind of surgery. The aim of this study is to investigate if a risk-adapted dose-
 and target-volume concept in clearly defined patient groups is possible to individualize
 postoperative radiotherapy without reducing locoregional-control but with reducing
 radiotherapy-related side-effects.

 There are two main issues to investigate:

 1. Dose prescription in primary tumor region:

 In this study it should be investigated if a dose reduction to 56 Gy in the primary
 tumor region is possible, if the resection margin is >= 5mm, tumor stage is <=pT2 and if
 there are no other risk factors like perineural spread or peritumoral lymphangiosis.

 2. Target volume definition in elective lymph node levels

 It should be investigated if ipsilateral cervical lymph irradiation alone allows
 adequate locoregional control in selected patients:

 ipsilateral lymph node metastasis <=3 and contralateral pN0 (adequate contralateral
 selective neck dissection performed) or contralateral cN0 (in patients with strictly
 ipsilateral localized tumors of the oral cavity or oropharynx)

 Considering these facts 3 therapy groups are possible:

 A:

 Criteria:

 -  pT2, R ≥ 5 mm, L0, Pn0

 -  3 lymph node metastasis or patients with < 3 ipsilateral lymph node metastasis
 and a bilateral primary tumor without adequate contralateral neck dissection

 Intervention:

 -  Reduction of radiation dose in the primary tumor region to 56 Gy,

 -  Elective Radiotherapy of both neck sides

 B:

 Criteria:

 •> pT2 and/or R < 5mm and/or L1 and/or Pn1

 •≤ 3 ipsilateral lymph node metastasis (and contralateral pN0 (>= 6 resected lymph
 nodes) or contralateral cN0 in patients wih strictly ipsilateral localised ( >= 5 mm
 distance from midline) cancer of the oral cavity or oropharynx

 Intervention

 •No dose reduction in primary tumor region (prescribed dose in primary tumor region: 64
 Gy)

 •Reduction of target volume: only elective radiotherapy of the ipsilateral neck, no
 contralateral neck irradiation

 C:

 Criteria

 -  pT2, R ≥ 5 mm, L0, Pn0

 -  3 ipsilateral lymph node metastasis (and contralateral pN0 (>= 6 resected lymph
 nodes) or contralateral cN0 in patients wih strictly ipsilateral localised ( >= 5
 mm distance from midline) cancer of the oral cavity or oropharynx

 Intervention

 •Reduction of radiation dose in the primary tumor region to 56 Gy, AND

 •Reduction of target volume: only elective radiotherapy of the ipsilateral neck, no
 contralateral neck irradiation

 In all arms the dose prescription for the lymph node regions is as follows:

 •elective lymph node level (either ipsi- or bilateral): 50 Gy

 •lymph node level with lymph node metastasis without extracapsular extension: 56Gy

 -  lymph node level with lymph node metastasis with extracapsular extension: 64 Gy

 In all arms simultaneously chemotherapy is recommended in the following cases:

 -  lymph node metastasis with extracapsular extension •>= 3 lymph node metastasis

 All patients are stratified according to HPV status.

 Additional investigations:

 -  swallowing endoscopy (before, 6 and 24 months after radiotherapy)

 -  translational research (especially individual radiosensitivity, immunologic
 parameters in peripheral blood during treatment)

 -  QoL
Inclusion Criteria:

 1. Histologic proven squamous cell carcinoma of the oral cavity/larynx/oro- or
 hypopharynx

 2. Postoperative tumor status:

 -  Oral cavity, oropharynx or larynx: pT1-3, pN0-pN2b

 -  Hypopharynx: pT1-2; pN1

 3. Patients that fulfill one or both of the following criteria:

 -  ≤ pT2, R ≥ 5 mm, L0, Pn0

 -  ≤ 3 ipsilateral lymph node metastases (if a contralateral adequate neck
 dissection is performed, no contralateral neck dissection is recommended in
 patients with strictly ipsilateral localised tumors of the oropharynx or oral
 cavity)

 4. R0-Resection (resection margin ≥ 1mm)

 5. No distant metastasis cM0

 6. age ≥ 18 years, no upper age limit

 7. ECOG ≤ 2

 8. Patients that understood protocol contents and are able to behave according to
 protocol

 9. Signed study-specific consent form prior to therapy

 10. In case of indicated simultaneous chemotherapy:

 -  adequate bone marrow function (leucocytes > 3,5x10^3, platelets > 100x 10^3,
 hemoglobin > 10g/dl

 -  sufficient liver function: bilirubin < 2,0mg/dl, ALT, AST < less than 3 times
 upper limit of normal

 -  sufficient renal function: normal serum creatinine, glomerular filtration rate >
 60ml/min

 Exclusion Criteria:

 1. pregnant or lactating/nursing women

 2. fertile patients that are not willing to use highly effective methods of contraception
 (per institutional standards) during treatment

 3. Any condition potentially hampering compliance with the study protocol and follow-up
 schedule

 4. On-treatment participation on other trials

 5. R1 or R2 resection status

 6. pN2c and pN3

 7. cM1

 8. prior radiotherapy in the head and neck region , prior chemo- or immunotherapy
 (neoadjuvant/induction)

 9. time between surgery and beginning of radio(chemo)therapy > 6 weeks

 10. Prior (> 4 months before beginning of radio(chemo)therapy) neck dissection

 11. In case of indicated simultaneous chemotherapy:

 -  reduced hearing ability (especially upper frequency range)

 -  known dihydropyrimidindehydrogenase (DPD) deficiency

 -  simultaneous therapy with brivudin or other DPD-inhibitors

 -  uncontrolled serious disease, including physical and mental diseases, for example
 within last 6 months:instable angina pectoris, heart attack, serious cardiac
 dysrhythmias, stroke, serious carotid stenosis, neurologic or psychiatric
 disorders including epilepsy, dementia, psychosis; uncontrolled infection; liver
 cirrhosis Child B or C, severe hepatic impairment; severe blood count changes;
 severe renal impairment, HIV