Definitive Chemo-Radiotherapy for Regionally Advanced Head and Neck Cancer With or Without Up-front Neck Dissection

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT02918955

Studienbeginn:
Oktober 2016

Letztes Update:
02.03.2023

Wirkstoff:
Chemotherapy (Cisplatin)

Indikation (Clinical Trials):
Head and Neck Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Insel Gruppe AG, University Hospital Bern

Collaborator:
University of Bern

Studienleiter

Olgun Elicin, MD
Study Chair
Department of Radiation Oncology, Inselspital

Kontakt

Olgun Elicin, MD
Kontakt:
Phone: +41 31 632 26 32
E-Mail: olgun.elicin@insel.ch» Kontaktdaten anzeigen

Timo Nannen, Study Nurse
Kontakt:
Phone: +41 31 632 90 74
E-Mail: upfrontneck@insel.ch» Kontaktdaten anzeigen

Studienlocations
(2 von 2)

Inselspital Bern
3010 Bern
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
OLGUN ELICIN, MD
Phone: +41 31 632 26 32
E-Mail: olgun.elicin@insel.ch» Ansprechpartner anzeigen

University Hospital of Geneva
1205 Geneva
SwitzerlandAbgeschlossen» Google-Maps

Studien-Informationen

Detailed Description:

The main objective of this project is to test the hypothesis that the addition of UFND prior

to (C)RT results in a significant reduction of treatment toxicities and improvement of QoL in

regionally advanced (cN2-3) HNSCC through dose de-escalation and volume reduction of RT.

The primary endpoint of this trial is to evaluate the toxicity from the beginning of

radiotherapy until 90 days after the end of the treatment. The incidence of acute and

subacute toxicities higher than grade ≥3 (CTCAE v.4, except for Xerostomia, for which

RTOG/EORTC scale will be used) will be compared between study arms. Secondary endpoints

include the survival endpoints for both treatment modalities; i.e. loco-regional control,

progression-free and overall survival. Assessment of QoL (EORTC QLQ-C30 + H&N43), late

toxicity, surgical complications, cost-effectiveness and the need of feeding-tube will be a

part of the final analysis of this trial.

Trial design: randomized multi-center open-label comparative one-staged phase III trial with

a superiority design and the primary endpoint of highest grade radiation toxicity during and

until 90 days after the completion of the treatment. Interventions in both arms of the trial

are considered as standard treatments. No experimental diagnostic tools will be used during

the trial. In addition to the randomized arms, two identical observational arms will be

opened for the patients who are diagnosed before the activation of the randomized arms, and

subsequently for those who refuse to be randomized. Their aim is to prospectively acquire

high quality data for patients who refuse randomization. The observational and randomized

cohorts will be analyzed separately for the pre-defined endpoints.

For the calculation of the sample size, grade ≥3 acute radiation toxicity in the CRT alone

(Arm A) was assumed as 70% based on literature. For the primary endpoint, a follow-up period

of 90 days after the last day of (C)RT is needed after the accrual of the last patient.

However, 2 years of follow-up after (C)RT is needed for the secondary endpoints (exception:

oncological outcome and survival will be calculated from the day of randomization in order to

avoid immortal time bias). On this basis, sample size was calculated based on the Pearson

chi-squared test and performed in Stata. Assuming a toxicity fraction of 70% for any grade 3

or higher toxicity in Arm A, a relative risk of 0.5 (35% in Arm B), a two-sided alpha of

0.05, a power of 80%, a drop-out rate of 5%, and an allocation ratio of 1 we calculated an

overall sample size of 65. Expected accrual time is 3 years.

Ein-/Ausschlusskriterien

1. Before patient registration/randomization, written informed consent must be given

according to ICH/GCP, and national/local regulations.

2. Patient should not be a participant in any interventional clinical trial.

3. Age ≥ 18 years.

4. WHO/ECOG performance status 0-2 within 28 days prior registration.

5. Histopathologically confirmed, previously untreated HNSCC of the oropharynx,

hypopharynx or larynx within 6 weeks (42 days) of registration.

6. No cT4 primary tumor destructing and/or breaching through bone and/or cartilage

(cortical invasion only is still eligible).

7. Clinical Nodal stage (cN) of at least cN1.

8. No evidence of distant metastases (cM0). No synchronous second primary HNSCC at the

time of diagnosis.

9. No synchronous or previous malignancies. Exceptions are adequately treated basal cell

carcinoma or SCC of the skin, or in situ carcinoma of the cervix uteri or breast with

a cancer-free follow-up time of at least 3 years, or other previous malignancy with a

disease-free interval of at least 5 years.

10. No prior radiotherapy to the head and neck region (or any RT fields/volumes which may

overlap with the intended therapy volumes).

11. No prior neck dissection or single lymph node excision is allowed.

12. History and physical examination by treating physician (head and neck surgeon, medical

oncologist or radiation oncologist) within 28 days prior registration.

13. Patients must have clinically and/or radiological documented measurable disease. At

least one site of disease must be unidimensionally measurable as per RECIST 1.1. All

imaging studies for staging must be performed within 28 days prior to registration.

14. Imaging of the head and neck (CT with contrast, PET/CT and/or MRI) within 28 days

prior to registration: A CT scan (as part of the PET/CT is also accepted), with

contrast is mandatory unless contraindicated (e.g. contrast allergy, renal

insufficiency etc.). Note that a PET/CT scan alone, unless performed with radio-opaque

contrast material is not sufficient for the CT-based evaluation of the head and neck

area.

15. PET/CT of the whole body within 28 days prior registration

16. QoL and toxicity evaluation completed within 28 days or at the time of registration.

Exceptions: 1) Language problems or any health problems interfering with the QoL

assessment. 2) Patients who want to be enrolled into the observational arms and refuse

to take part in the QoL assessments.

17. Patients with a contraindication against neck dissection are not eligible (e.g.

medical co-morbidities, positive lymph node conglomerates enclosing and infiltrating

carotid artery or merging with the primary tumor)

18. The patient must be expected to withstand neck dissection and radiotherapy combined

with cisplatin.

19. Preservation of the accessory nerve during neck dissection should be possible.

Patients expected to have a permanent shoulder dysfunction because of a planned

sacrifice of the accessory nerve are not eligible.

20. Laboratory requirements within 28 days prior to accrual:

1. Adequate renal function: Serum creatinine ≤1.5 mg/dL and/or creatinine clearance

>50 mL/min estimated within 28 days prior accrual

2. Absolute neutrophil count (ANC) ≥1.0 x 109/L

3. Platelet count ≥75 x 109/L

4. Hemoglobin ≥10 g/dL or 6.2 mmol/L (Note: The use of transfusion to achieve Hgb

≥10 g/dL is acceptable)

5. Bilirubin <1.5 times of upper limit of normal (ULN), aspartate aminotransferase

(AST) and alanine aminotransferase (ALT) <3 times of ULN.

21. Women are not breastfeeding. Women with Child-bearing potential and using effective

contraception (see Section 5.6), and not pregnant and agree not to become pregnant

during participation in the trial and 2 years after chemoradiotherapy. A negative

pregnancy test before inclusion (within 28 days) into the trial is required for all

women with child-bearing potential. Men agree not to father a child during

participation in the trial and 2 years after chemoradiotherapy.

22. No allergy to study drugs or to the excipients in their formulation.

23. No peripheral neuropathy ≥grade 2 according to CTCAE v4.03 (grade 2 = moderate

symptoms limiting instrumental ADL)

24. No co-existing disease prejudicing survival (expected survival <6 months).

25. No severe cardiac illness: Myocardial infarction within 6 months prior to

randomization, severe congestive heart failure, severe cardiomyopathy, ventricular

arrhythmia, unstable angina, uncontrolled hypertension.

26. No active bacterial or fungal infection requiring intravenous antibiotics at the time

of registration

27. No Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness

requiring hospitalization or precluding study therapy within 28 days before

registration.

28. No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

29. No clinically manifested Acquired Immune Deficiency Syndrome (AIDS) or

immune-compromised patients. Note, however, that HIV testing is not required for entry

into this protocol. The need to exclude patients with AIDS from this protocol is

necessary because the treatments involved in this protocol may be significantly

immunosuppressive.

Absence of any psychological, familial, sociological or geographical condition potentially

hampering compliance with the study protocol and follow-up schedule; those conditions

should be discussed with the patient before registration in the trial.

Studien-Rationale

Primary outcome:

1. Number of patients with acute & subacute toxicity based on CTCAE scoring system v4.03 (Time Frame - from the beginning of radiotherapy until 90 days after the end of the treatment)

Secondary outcome:

1. Number of patients with late Toxicity based on CTCAE scoring system v4.03 (Time Frame - beginning from 91 days after the end of radiotherapy until the end of the 2 years follow up)

2. Change from baseline quality of life(QoL)using EORTC QLQ-C30 v3&EORTC QLQ-H&N43 modules(Health related QoL specific for Head&Neck ca.)scores at end of RT, 3,12&24 months after RT.Swallowing (H&N43:4-item scale)3 months after RT is the primary QoL domain (Time Frame - up to 24-28 months depending on the treatment duration.):
EORTC QLQ-C30 and H&N43 will be used

3. Loco-regional control (Time Frame - 2 years from the randomization)

4. Progression-free survival (Time Frame - 2 years from the randomization)

5. Overall survival (Time Frame - 2 years from the randomization)

6. Distant metastasis-free survival (Time Frame - 2 years from the randomization)

7. Disease-specific survival (Time Frame - 2 years from the randomization)

8. QoL comparison between the patients who accepted to be randomized (into rA and rB) and not (into oA and oB: in other words, patients who chose their own treatment strategy) (Time Frame - Baseline QoL and until the end of 2 years follow-up)

9. Surgical complication rates (Time Frame - 2 years from the randomization)

10. Rate of Isolated nodal control (Time Frame - 2 years from the randomization):
The absence of metastatic lymph node metastases in the neck without any synchronous or preceding local recurrence or distant metastases

11. Radiation dose and volumes (Time Frame - until the end of radiotherapy, expected to be on average 7 weeks):
The dose-volume histograms of all organs-at-risk (defined per protocol) will be compared between patients with and without up-front neck dissection. The doses will be reported in Gy and the volumes in cc.

12. Comparison of applied RT plan and the virtual RT plan done on the pre-UFND diagnostic CT images (Time Frame - until the end of radiotherapy, expected to be on average 7 weeks):
The dose-volume histograms of all organs-at-risk (defined per protocol) will be compared between the plans generated based on the pre- and post-UFND CT-scans of patients allocated the UFND arm. The doses will be reported in Gy and the volumes in cc.

13. Comparison between clinical and pathological stages of patients allocated to the UFND arm. according to the AJCC/UICC TNM staging system (7th edition). (Time Frame - until the generation of the definitive pathology report after the up-front neck dissection, expected to be within 3 weeks after patients' study enrollment)

Studien-Arme

Active Comparator: Arm rA (randomized)
Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response
Experimental: Arm rB (randomized)
Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery
Active Comparator: Arm oA (non-randomized)
Concomitant chemo-radiotherapy with early salvage neck dissection if less than complete clinical response
Experimental: Arm oB (non-randomized)
Up-front neck dissection followed by radiotherapy with concomitant chemotherapy based on the cT pN cM staging after surgery

Geprüfte Regime

up-front neck dissection
radiotherapy:
70 Gy in 35 fractions to the macroscopic disease 50 Gy in 25 fractions (if sequential boost) or 56 Gy in 35 fractions (if simultaneous integrated boost) to the elective volumes 66 Gy in 35 fractions to the post-operative region with lymphatic extracapsular extension (Arm B only)
Chemotherapy (Cisplatin):
100 mg/m2 every three weeks during radiotherapy In Arm B, chemotherapy can be omitted in case of a cT1-2 primary and a surgical downstaged pN0-1 neck without lymphatic extracapsular extension.
Early Salvage Neck Dissection in case of less than cCR (Arm A only):
Early salvage neck dissection in case of residual lymph node disease will be performed based on the response evaluation by MRI and PET/CT performed 3 and 4 months after the end of (chemo)radiotherapy, respectively (and additional diagnostic modalities if clinically indicated by the physician) and not more than 3 weeks after this post-radiotherapy evaluation. In Arm A, a successful early salvage neck dissection without the operation of the primary tumor in case of less than clinical complete response (cCR) will be considered a component of the multimodality treatment and not as a failure.

Quelle: ClinicalTrials.gov

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