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

Not Applicable

Terminated

• Conditions: Head and Neck Neoplasm
• Interventions: Radiation: Stereotactic body radiotherapy

• Registration Number: NCT03402737
• Lead Sponsor: University Hospital, Ghent

Brief Summary

To derive the maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck.

Detailed Description

The standard treatment in inoperable locally or regionally recurrent head and neck cancer has long been palliative systemic therapy using the so-called EXTREME-scheme: a combination of cisplatin, 5-fluorouracil and cetuximab. This therapy remains without realistic chances of cure. More recently, immunotherapy using nivolumab has demonstrated to result in long-term disease control of 1-2 year in cisplatin-refractory recurrent or metastatic head and neck cancer, however only in a small portion of patients (13%).

Fractionated high-dose local or regional re-irradiation is mostly given in a 6-7 weeks scheme. Using stereotactic body radiotherapy (SBRT), high radiotherapy doses can be given in a short time span. Severe late adverse events have been reported using SBRT but seem less frequent than in patients re-treated with conventional schedules. A possible solution to be able to administer higher doses is combining SBRT with dose painting, thus giving these high doses on small subvolumes only.

Addition of concomitant therapy to reirradiation may further improve outcomes due to radiosensitization and direct cytotoxicity. Therefore the investigator aims to combine high doses with concomitant therapy in the proposed study.

The immunomodulatory effect caused by radiation has been demonstrated both in animal models and clinical trials and leads to an enhanced local control as well as to eradication of distant metastasis. This so-called abscopal effect is reached through a systemic immune response evoked by the release of damage-associated molecular patterns (DAMPs) by the dying tumor-cells, also called immunogenic cell death (ICD).

The investigator hypothesizes that an abscopal effect could be present for patients presenting locoregional recurrent disease with asymptomatic distant metastases, thereby offering at least symptom control at the primary site while palliative systemic treatment could be postponed.

The proposed protocol focuses on patients with bad prognosis, as determined by a short timespan between primary therapy and recurrence (defined as 6-24 months after the end of the primary radiotherapy). It would bring the practical advantage of only 2-3 patient visits for the radiotherapy instead of ± 30-35 visits over 6-7 weeks. This shorter treatment schedule is expected to result in a direct gain in quality-of-life due to locoregional symptom control. It can also be expected that rescue systemic therapy will be postponed to a later stage of disease development, thereby prolonging overall survival.

The combination with systemic agents that are involved in immunogenic cell death bear the potential to result in a higher number of patients with longer periods of disease control and survival. The current standard of care, i.e. the combined systemic treatment with cisplatin - 5-fluorouracil - cetuximab, or nivolumab in case of former cisplatin use, can be used as a rescue regimen in case of therapy failure. In that sense, better overall survival from time of diagnosis of the index locoregional recurrent disease is expected.

Study Timeline

• Study Start: 2017-07-31
• Study First Submitted: 2017-11-20
• Study First Submitted QC: 2018-01-10
• Study First Posted: 2018-01-18
• Primary Completion: 2020-12-03
• Study Completion: 2020-12-03
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-16
• Last Update Posted: 2021-02-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 6

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Stereotactic body radiotherapy + IM	Stereotactic body radiotherapy	Single arm phase I trial with 3 Stereotactic Body Radiation Therapy dose-escalation arms.

Primary Outcome Measures

Name	Time	Method
maximum tolerated dose	3 months after radiotherapy	maximum tolerated dose of hypofractionated stereotactic body radiotherapy (SBRT) using dose painting by numbers with immunomodulating systemic therapy in patients that are reirradiated for recurrent squamous cell carcinoma of the head and neck

Secondary Outcome Measures

Name	Time	Method
symptom palliation - dysphagia	through study completion, an average of 12 months	reduction in grade of dysphagia
grade ≥ 3 toxicity-free survival	through study completion, an average of 12 months	To estimate grade ≥ 3 toxicity-free survival (anemia, febrile neutropenia, fatigue, dysphagia, oral mucositis, laryngeal mucositis, pharyngeal mucositis, pharyngeal hemorrhage, pharyngeal necrosis, pharyngeal stenosis, pharyngolaryngeal pain, dry mouth)
immune response	using serum taken before treatment and at each fraction of SBRT, at weeks 6-14	To assess the immune response
local control	3 months after SBRT and thereafter through study completion, an average of 12 months	Assessment of: 1. diameter of target lesion of SBRT (and, if present, non-target lesions) in mm; 2. tumor response according to recist criteria
Progression free survival	through study completion, an average of 12 months	To estimate progression-free survival
symptom palliation - pain	through study completion, an average of 12 months	reduction in pain
Overall survival	through study completion, an average of 12 months	To estimate overall survival
QOL - general	before therapy, week 3, week 6, week 10, week 14	To assess quality-of-life: EORTC QLQ
QOL - H&N specific	before therapy, week 3, week 6, week 10, week 14	To assess quality-of-life: H\&N35
topographic distribution of recurrence	through study completion, an average of 12 months	To assess the topographic distribution of recurrence (inside/outside FDG-avid GTV)
time to further treatment	through study completion, an average of 12 months	To assess time to further treatment

Trial Locations

Locations (3)

UZ Leuven; 🇧🇪 Leuven, Belgium

CHU Namur; 🇧🇪 Namur, Belgium

Radiotherapy department, University Hospital Ghent; 🇧🇪 Ghent, Oost-Vlaanderen, Belgium