SBRT + Immunomodulating Systemic Therapy for Inoperable, Recurrent H&N

Inclusion Criteria:

* Histologically confirmed local, regional or combined locoregional recurrence of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx or cancer of unknown primary (CUP) in the neck in previously irradiated tissue, with former irradiation with curative intent.
* Patients with non-symptomatic distant metastases and local, regional or combined locoregional recurrence can be included.
* In case of non-metastatic disease, the recurrence must be primarily unresectable recurrence and/or patients refused surgery.
* Time interval 6-24 months after the end of the initial radio(chemo)therapy for primary head and neck cancer.
* Decision of the Head and Neck Tumor Boards at the recruiting centre to offer salvage radio(chemo)therapy, palliative chemotherapy or anti-PD-1 antibody treatment with nivolumab for cisplatin-refractory locoregional recurrent head and neck squamous cell carcinoma.
* Karnofsky performance status ≥ 70.
* Age ≥ 18 years old.
* Informed consent obtained, signed and dated before specific protocol procedures.

Exclusion Criteria:

* Previous radiotherapy was for cT1-2 cN0 M0 glottic cancer.
* Grade ≥ 4 late toxicity after the initial radio(chemo)therapy.
* Brachytherapy as treatment for second primary / recurrence.
* Previous (combination with) immunotherapy for the primary or the recurrent squamous cell carcinoma.
* Impossibility of oral intake of cyclophosphamide.
* For patients receiving cyclophosphamide: necessary intake during therapy of allopurinol, amiodarone, digoxin, hydrochlorothiazide, indomethacin, phenobarbital, phenytoin, warfarin. clopidogrel, ticlopidine, carbamazepine, efavirenz, rifampicin, ritonavir
* High risk for arterial blow-out: 1 of following criteria is sufficient to exclude patients:

  1. soft tissue necrosis
  2. skin invasion of the recurrent cancer
  3. circumferential involvement of \> 180° of a carotid artery
* Symptomatic distant metastases.
* Other uncontrolled second primary tumors.
* Pregnant or lactating women.
* Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
* Patient unlikely to comply with protocol, i.e. uncooperative attitude, inability to return for follow-up visits, and unlikely to complete the study.