Dose De-escalation and Sentinel Lymph Node Mapping Driven Radiotherapy of Contralateral Neck in cN1-2 HNSCC
Dose De-escalation and Sentinel Lymph Node Mapping Driven Radiotherapy of Contralateral Neck in cN1-2 HNSCC
The study involves head and neck squamous cell carcinomas (HNSCC) of the oral cavity,
 oropharynx, larynx or hypopharynx with positive nodes on only one side of the neck and no
 distant metastasis treated by primary (chemo)radiotherapy.

 The elective node irradiation on the contralateral side is not always mandatory and the dose
 may be too high. In this study, we evaluate two strategies: the impact of sentinel lymph node
 mapping to tailor the volumes to irradiate and the dose reduction.
The risk of lymph drainage to the contralateral side of the neck is limited to maximum 50% of
 the patients. Moreover, the risk of occult metastases lies between 20 and 40%. As a
 consequence, the rule of irradiating the contralateral neck with a prophylactic intent
 ("elective nodal irradiation") in nearly all HNSCC patients roughly doubles the irradiated
 volume and, hence, increases the risk of developing more frequent and more severe acute and
 late side effects. The use of sentinel lymph node mapping to assess the contralateral side of
 the neck should help to determine the individual drainage to the contralateral side of the
 neck and, in case of drainage, determine which nodes need to be irradiated. The ultimate goal
 is to reduce the volume irradiated at prophylactic dose to decrease the risk of severe late
 side effects (volume de-escalation strategy). This strategy is proposed based on the recent
 completion of a similar study led by the coordinating investigator, together with the head
 and neck team of the CHU-UCL-Namur, in HNSCC patients without macroscopic nodes in the neck
 and treated with (chemo)radiotherapy. It was shown that sentinel lymph node mapping helped to
 safely individualize and de-escalate the elective nodal irradiation volume and significantly
 reduce the risk of severe late side effects. Anyway, it is unknown if the whole sub-region of
 the neck containing the sentinel lymph node(s) or the node(s) only should be defined as
 target volume.

 Moreover, the dose used nowadays for elective nodal irradiation, i.e. 50 Gy in fractions of 2
 Gy or biologically equivalent, dates back from the 70's. Many arguments (a.o. our better
 capacity to stage the neck with 3D imaging and the use of concomitant chemotherapy in the
 majority of node-positive HNSCC) are in favour of dose de-escalation. A multicentric
 randomized study performed in 100 HNSCC recently showed that the elective dose could be
 reduced to 40 Gy in fractions of 2 Gy or biologically equivalent, helping to reduce the risk
 of late dysphagia at 6 months post-radiotherapy. Confirmatory studies need to be performed on
 larger groups of patients.

 The primary aim is to evaluate contralateral regional control (cRC) rate at 2 years in head
 and neck squamous cell carcinomas (HNSCC) of the oral cavity, oropharynx, larynx or
 hypopharynx with positive nodes on only one side of the neck and no distant metastasis
 treated by (chemo)radiotherapy applying a dose- and/or volume de-escalation.
Inclusion Criteria:

 1. Written informed consent given according to ICH/GCP and national/local regulations
 must be obtained prior to any screening procedures.

 2. World Health Organization (WHO) performance status 0-1.

 3. Age ≥ 18 years.

 4. Patients with a pathologically proven invasive HNSCC, including oral cavity,
 oropharynx (independently of HPV status), larynx or hypopharynx.

 5. Decision by Multidisciplinary Tumor Board of primary treatment with radical
 radiotherapy with or without concurrent chemotherapy (according to the local
 guidelines).

 6. Baseline imaging of the neck:

 -  a. ≤ 2.5 mm slices CT with iodine injection (independently or during the
 FDG-PET/CT examination IF acquired in normal diagnostic conditions, i.e. arms
 along the thorax with diagnostic quality);

 -  b. MRI not mandatory but allowed, performed according to centres guidelines;

 -  c. FDG-PET/CT.

 7. Tumor characteristics:

 1. cT-classification (8th TNM staging): T1(except T1 of glottis)-T3.

 2. cN-classification (8th TNM staging), as assessed by iodine contrasted CT (or MRI)
 and FDG-PET:

 i. mandatorily cN0 contralaterally to the primary tumor (or on one side of the neck
 for midline primary tumors):

 1. smallest diameter < 5 mm in retropharyngeal level (VIIa); 2. smallest diameter of
 Küttner node (level IIa) < 12 mm; 3. smallest diameter < 10 mm or sum of smallest and
 largest diameters < 17 mm in any other level; 4. no central necrosis ; 5. maximal
 standardized uptake value (SUVmax) ≤ 2.2; 6. in dubious cases (typically 2.2 < SUVmax < 4.5
 and inconclusive CT or MRI), US-guided FNAC may be required to exclude positive node
 contralaterally.

 ii. ipsilaterally positive (if any of the above mentioned criteria is met). c. No distant
 metastasis.

 Exclusion Criteria:

 1. Patient has history of:

 1. radiotherapy or surgery in the neck with potential impact on lymphatic drainage
 ("violated neck");

 2. cancer in the last five years (excluding skin basal cell carcinoma and in situ
 cervix carcinoma);

 3. Absolute contra-indication to iodine contrast injection, even after proper
 cortisone and cetirizine pre-medication.

 2. HNSCC from nose, sinuses, oesophagus, salivary glands or nasopharynx.

 3. Non-HNSCC histology.

 4. Positive contralateral neck by node size or positive US-FNAC in dubious nodes.

 5. Synchronous second malignancy.

 6. Distant metastasis.

 7. Tumor crossing the midline without contralateral mapping after 99mTc-nanocolloïd
 injection.

 8. Any psychological disorder or familial, sociological or geographical condition which,
 in the investigator's opinion, might jeopardise participant's safety or compliance
 with the protocol.

 9. Female who is pregnant, breast-feeding or intends to become pregnant or is of
 child-bearing potential and not using an adequate contraceptive method.

 Highly effective methods of birth control are defined as those, alone or in combination,
 that result in a low failure rate (i.e., less than 1% per year) when used consistently and
 correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true
 sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period
 of risk associated with the Trial treatments) or vasectomised partner.