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Dose De-escalation and Sentinel LN Mapping Driven Radiotherapy of Contralateral Neck in Ipsilateral Node Positive HNSCC (SEMIRAHN)

Primary Purpose

Squamous Cell Carcinoma of Head and Neck

Status
Recruiting
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
Dose de-escalation and / or Volume de-escalation
Sponsored by
Universitaire Ziekenhuizen KU Leuven
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Squamous Cell Carcinoma of Head and Neck focused on measuring HNSCC, Dose and Volume de-escalation in radiotherapy, sentinel lymph nodes mapping

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • ZOLRecruiting
  • Jessa ZiekenhuisRecruiting
  • OLV AalstRecruiting
  • UCL Saint-LucRecruiting
  • Institute Jules BordetRecruiting
  • University Hospital GentRecruiting
  • Universitaire Ziekenhuizen LeuvenRecruiting
  • AZ Sint-MaartenRecruiting
  • CHU-UCL NamurRecruiting
  • AZ TurnhoutRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Arm A: Unilateral RT

Arm B: Whole level

Arm C: SLN alone

Arm Description

If SPECT/CT shows ipsilateral drainage and the tumor does not cross the midline, the subject will automatically be assigned to Arm A, and will receive ipsilateral Radiotherapy with reduced prophylactic dose outside of the macroscopically involved nodes. The contralateral side of the neck will be spared according to the absence of sentinel lymph node drainage.

If SPECT/CT shows contralateral drainage, the subject will be randomized between 'Whole level' and 'SLN alone'. Arm B 'Whole Level': on the contralateral side of the neck, the whole level(s) containing the draining sentinel lymph node(s) will be irradiated at the reduced prophylactic dose. The ipsilateral side of the neck will be irradiated conform to arm A.

If SPECT/CT shows contralateral drainage, the subject will be randomized between 'Whole level' and 'SLN alone'. Arm C 'SLN alone': on the contralateral side of the neck, only the sentinel node(s) will be irradiated at the reduced prophylactic dose. The ipsilateral side of the neck will be irradiated conform to arm A.

Outcomes

Primary Outcome Measures

Contralateral regional control (cRC) rate at 2 years
The rate of tumor control in the draining nodal regions of the neck.

Secondary Outcome Measures

Questionnaire assessing the quality of life of patients with head and neck cancer
Measured by the EORTC QLQ-H&N35 questionnaire.
Questionnaire assessing the quality of life of cancer patients.
Measured by the EORTC QOL-C30 (version3) questionnaire.
Normal tissue complication probability (NTCP) gain estimation
Estimation of the difference in risk of complications for xerostomia, dysphagia and hypothyroidism according to validated NTCP models.
Local Control
Loco-regional control (LRC)
Survival
Cancer specific survival
Survival
Overall survival
Radiotherapy induced toxicity
Acute and Late Toxicity Scoring

Full Information

First Posted
December 18, 2020
Last Updated
May 10, 2023
Sponsor
Universitaire Ziekenhuizen KU Leuven
Collaborators
Stichting tegen Kanker, KU Leuven
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1. Study Identification

Unique Protocol Identification Number
NCT04688528
Brief Title
Dose De-escalation and Sentinel LN Mapping Driven Radiotherapy of Contralateral Neck in Ipsilateral Node Positive HNSCC
Acronym
SEMIRAHN
Official Title
A Prospective Randomized Phase 2 Study of Dose and Volume De-escalation Radiotherapy With Sentinel Lymph Nodes Mapping for Contralateral Irradiation in Unilaterally Node Positive Head and Neck Squamous Cell Carcinomas (SEMIRAHN)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 10, 2021 (Actual)
Primary Completion Date
January 2027 (Anticipated)
Study Completion Date
January 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Universitaire Ziekenhuizen KU Leuven
Collaborators
Stichting tegen Kanker, KU Leuven

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Squamous Cell Carcinoma of Head and Neck
Keywords
HNSCC, Dose and Volume de-escalation in radiotherapy, sentinel lymph nodes mapping

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
147 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A: Unilateral RT
Arm Type
Experimental
Arm Description
If SPECT/CT shows ipsilateral drainage and the tumor does not cross the midline, the subject will automatically be assigned to Arm A, and will receive ipsilateral Radiotherapy with reduced prophylactic dose outside of the macroscopically involved nodes. The contralateral side of the neck will be spared according to the absence of sentinel lymph node drainage.
Arm Title
Arm B: Whole level
Arm Type
Experimental
Arm Description
If SPECT/CT shows contralateral drainage, the subject will be randomized between 'Whole level' and 'SLN alone'. Arm B 'Whole Level': on the contralateral side of the neck, the whole level(s) containing the draining sentinel lymph node(s) will be irradiated at the reduced prophylactic dose. The ipsilateral side of the neck will be irradiated conform to arm A.
Arm Title
Arm C: SLN alone
Arm Type
Experimental
Arm Description
If SPECT/CT shows contralateral drainage, the subject will be randomized between 'Whole level' and 'SLN alone'. Arm C 'SLN alone': on the contralateral side of the neck, only the sentinel node(s) will be irradiated at the reduced prophylactic dose. The ipsilateral side of the neck will be irradiated conform to arm A.
Intervention Type
Radiation
Intervention Name(s)
Dose de-escalation and / or Volume de-escalation
Intervention Description
The dose de-escalation and/or volume de-escalation strategy will be individually adapted in function of the draining pattern of sentinel lymph nodes on the contralateral side of the neck.
Primary Outcome Measure Information:
Title
Contralateral regional control (cRC) rate at 2 years
Description
The rate of tumor control in the draining nodal regions of the neck.
Time Frame
From baseline to 2 years after radiotherapy
Secondary Outcome Measure Information:
Title
Questionnaire assessing the quality of life of patients with head and neck cancer
Description
Measured by the EORTC QLQ-H&N35 questionnaire.
Time Frame
From baseline to every 2 months in the first year and every 3 months in the second year after radiotherapy.
Title
Questionnaire assessing the quality of life of cancer patients.
Description
Measured by the EORTC QOL-C30 (version3) questionnaire.
Time Frame
From baseline to every 2 months in the first year and every 3 months in the second year after radiotherapy.
Title
Normal tissue complication probability (NTCP) gain estimation
Description
Estimation of the difference in risk of complications for xerostomia, dysphagia and hypothyroidism according to validated NTCP models.
Time Frame
Time from RT up to 2 years after RT.
Title
Local Control
Description
Loco-regional control (LRC)
Time Frame
Time from RT until local progression or death whichever comes first, up to 2 years after RT.
Title
Survival
Description
Cancer specific survival
Time Frame
Time from RT until the occurrence of a new tumor or death whichever comes first, up to 2 years after RT.
Title
Survival
Description
Overall survival
Time Frame
Time from RT until death from any cause
Title
Radiotherapy induced toxicity
Description
Acute and Late Toxicity Scoring
Time Frame
Time from start of RT up to 2 years after RT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria Written informed consent given according to ICH/GCP and national/local regulations must be obtained prior to any screening procedures. World Health Organization (WHO) performance status 0-1. Age ≥ 18 years. Patients with a pathologically proven invasive HNSCC, including oral cavity, oropharynx (independently of HPV status), larynx or hypopharynx. Decision by Multidisciplinary Tumor Board of primary treatment with radical radiotherapy with or without concurrent chemotherapy (according to the local guidelines). Baseline imaging of the neck: ≤ 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); MRI not mandatory but allowed, performed according to centres guidelines; FDG-PET/CT. Tumor characteristics: cT-classification (8th TNM staging): T1(except T1 of glottis)-T4a (or, for p16+ oropharyngeal tumors classified cT4, if criteria are compatible with cT4a-stage of p16- tumors). 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), i.e. cN1, cN2a, cN2b, ipsilateral cN3b; or cN1 for oropharyngeal p16+ tumors. No distant metastasis. Exclusion criteria Patient has history of: radiotherapy or surgery in the neck with potential impact on lymphatic drainage ("violated neck"); cancer in the last five years (excluding skin basal cell carcinoma, in situ cervix carcinoma and T1 of glottis or lip, completely chirurgically resected (R0) without intervention disturbing cervical lymph drainage); Absolute contra-indication to iodine contrast injection, even after proper cortisone and cetirizine pre-medication. HNSCC from nose, sinuses, oesophagus, salivary glands or nasopharynx. Non-HNSCC histology. Positive contralateral neck by node size or positive US-FNAC in dubious nodes. Synchronous second malignancy. Distant metastasis. Tumor crossing the midline without contralateral mapping after 99mTc-nanocolloïd injection. Tumor too large to be safely injected, as deemed by the surgeon. In case of doubt, contact may always be taken with the national coordinating investigator to discuss the situation and take a final decision. 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-François Daisne, MD, PhD
Phone
+32-16-34-76-00
Email
jean-francois.daisne@uzleuven.be
First Name & Middle Initial & Last Name or Official Title & Degree
Chris Bruyninckx, BA
Phone
+32-16-34-76-00
Email
chris.bruyninckx@uzleuven.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-François Daisne, Prof. Dr.
Organizational Affiliation
Universitaire Ziekenhuizen KU Leuven
Official's Role
Principal Investigator
Facility Information:
Facility Name
ZOL
City
Genk
State/Province
Limburg
ZIP/Postal Code
3600
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Liesbeth Raymakers
Email
studies.radiotherapy@jessazh.be
First Name & Middle Initial & Last Name & Degree
Elien Scherpenberg
Email
studies.radiotherapy@jessazh.be
First Name & Middle Initial & Last Name & Degree
Annelies Maes, MD
First Name & Middle Initial & Last Name & Degree
Mieke Govers, MD
First Name & Middle Initial & Last Name & Degree
Anne-Sophie Van de Velde, MD
Facility Name
Jessa Ziekenhuis
City
Hasselt
State/Province
Limburg
ZIP/Postal Code
3500
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Liesbeth Raymakers
Email
studies.radiotherapy@jessazh.be
First Name & Middle Initial & Last Name & Degree
Elien Scherpenberg
Email
studies.radiotherapy@jessazh.be
First Name & Middle Initial & Last Name & Degree
Annelies Maes, MD
First Name & Middle Initial & Last Name & Degree
Mieke Govers, MD
First Name & Middle Initial & Last Name & Degree
Anne-Sophie Van de Velde, MD
Facility Name
OLV Aalst
City
Aalst
ZIP/Postal Code
9300
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laurien De Waele
Email
laurien.de.waele@olvz-aalst.be
First Name & Middle Initial & Last Name & Degree
Sofie Tombeur
Email
sofie.tombeur@olvz-aalst.be
First Name & Middle Initial & Last Name & Degree
An Vancleef
Facility Name
UCL Saint-Luc
City
Brussel
ZIP/Postal Code
1200
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eléonore Longton
Email
eleonore.longton@saintluc.uclouvain.be
First Name & Middle Initial & Last Name & Degree
Eléonore Longton
Facility Name
Institute Jules Bordet
City
Brussel
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clémence Al Wardi
Email
clemence.alwardi@bordet.be
First Name & Middle Initial & Last Name & Degree
Dirk Van Gestel, MD, PhD
Facility Name
University Hospital Gent
City
Gent
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Frederic Duprez
Email
frederic.duprez@uzgent.be
First Name & Middle Initial & Last Name & Degree
Frederic Duprez, MD, PhD
Facility Name
Universitaire Ziekenhuizen Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chris Bruyninckx
Email
chris.bruyninckx@uzleuven.be
First Name & Middle Initial & Last Name & Degree
Rita Aerts
Email
rita.aerts@uzleuven.be
First Name & Middle Initial & Last Name & Degree
Jean-François Daisne, MD, PhD
First Name & Middle Initial & Last Name & Degree
Sandra Nuyts, MD, PhD
Facility Name
AZ Sint-Maarten
City
Mechelen
ZIP/Postal Code
2800
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Julie van der Veen
Email
Julie.van.der.Veen@emmaus.be
First Name & Middle Initial & Last Name & Degree
Julie van der Veen
Facility Name
CHU-UCL Namur
City
Namur
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Monique Gilsoul
Email
monique.gilsoul@chuuclnamur.uclouvain.be
First Name & Middle Initial & Last Name & Degree
Stéphanie Deheneffe, MD
First Name & Middle Initial & Last Name & Degree
Gilles Delahaut, MD
First Name & Middle Initial & Last Name & Degree
Stéphanie Gabriel, MD
Facility Name
AZ Turnhout
City
Turnhout
ZIP/Postal Code
2300
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nel Bovin
Email
Nel.Bovin@azturnhout.be
First Name & Middle Initial & Last Name & Degree
Michel Martens
First Name & Middle Initial & Last Name & Degree
Cedric Peters

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
24885222
Citation
Daisne JF, Installe J, Bihin B, Laloux M, Vander Borght T, Mathieu I, Lawson G. SPECT/CT lymphoscintigraphy of sentinel node(s) for superselective prophylactic irradiation of the neck in cN0 head and neck cancer patients: a prospective phase I feasibility study. Radiat Oncol. 2014 May 28;9:121. doi: 10.1186/1748-717X-9-121.
Results Reference
background
PubMed Identifier
32294522
Citation
Longton E, Lawson G, Bihin B, Mathieu I, Hanin FX, Deheneffe S, Vander Borght T, Laloux M, Daisne JF. Individualized Prophylactic Neck Irradiation in Patients with cN0 Head and Neck Cancer Based on Sentinel Lymph Node(s) Identification: Definitive Results of a Prospective Phase 1-2 Study. Int J Radiat Oncol Biol Phys. 2020 Jul 15;107(4):652-661. doi: 10.1016/j.ijrobp.2020.03.021. Epub 2020 Apr 12.
Results Reference
result

Learn more about this trial

Dose De-escalation and Sentinel LN Mapping Driven Radiotherapy of Contralateral Neck in Ipsilateral Node Positive HNSCC

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