Comparison of Two Concomitant Administration of RT With Cisplatin in Standard Infusion or Fractional Infusion (CisFRad)

Phase II Randomized Trial Comparating Two Concomitant Administration of Radiotherapy With Cisplatin in Patients With Not Operated or Inoperable HNSCC or With Recurrence High Risk in Adjuvant Postoperative Treatment

The general aim is to compare the cumulative dose of cisplatin administered concomitantly with radiotherapy in reference arm A (cisplatin 100 mg / m2 day 1 every 21 days) and in the experimental arm B (Cisplatin split 25 mg / m2 / J D1 to D4 all 21 days).

Study Overview

• Status: Completed
• Conditions: Squamous Cell Carcinoma of the Head and Neck
• Intervention / Treatment: Drug: Split Cisplatin; Radiation: Radiotherapy; Drug: Cisplatin

Detailed Description

The standard treatment for squamous cell carcinoma of the head and neck locally advanced non-operated or non-operable is a combination of radiotherapy and concomitant chemotherapy. Indeed, the meta-analysis MACH showed for RT / CT associations an absolute survival benefit of 8% compared with radiotherapy alone. Cisplatin delivered optimally, ie at a dose of 100 mg / m2 on day 1, D22 and D43 of radiotherapy is as effective as combinations of cisplatin and 5-fluorouracil.

In post operative, treatment of high risk recurrence forms by Cisplatin, concomitantly with radiotherapy, also increases local control and overall survival.

However, it is an association whose toxicity is significant. The usual limiting toxicities were mucositis, dysphagia, nausea and vomiting with malnutrition and biologically kidney failure and myelotoxicity. Only 2/3 of the patients receive 3 cycles of cisplatin initially programmed.

As shown in the RTOG 0129 trial, the number of cycles of cisplatin and thus the cumulative dose of cisplatin administered concurrently with radiation therapy, significantly influences the locoregional control, progression free survival and overall survival.

One method of reducing the toxicity and thereby, increase the cumulative dose, would be to split the administration of cisplatin.

Moreover, the efficacy of Cisplatin, which only the free fraction is active, seems correlated with AUC that peak plasma which would in turn responsible for toxicity. The completion of a pharmacokinetic study comparing the AUC and Cmax obtained with cisplatin 100 mg / m2 and cisplatin fractionated is essential.

Finally, the limiting renal toxicity induced by cisplatin is currently diagnosed using the creatinine clearance. The Neutrophil gelatinase-associated lipocalin (NGAL) urinary is a new diagnosis and prognosis marker of renal impairment following treatment with cisplatin. However, further studies are needed to validate its clinical utility.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Strasbourg, France, 67065
    • Centre Paul Strauss

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Squamous cell carcinoma of head and neck cancer stage III or IV: oral cavity, oropharynx, larynx or hypopharynx.
• Patient non-operated and / or inoperable for reasons of non extirpabilité, local and regional expansion, general state or medical condition Or
• Patient operated within 8 weeks before radiation therapy with a high risk of recurrence: unsatisfactory surgical margins (R1) and / or lymph node involvement with capsular rupture.
• Activity Index according to WHO ≤ 2
• Age ≤ 70 years
• Ventricular ejection fraction left retained> 50%
• Renal allowing the administration of cisplatin: creatinine clearance> 60 ml / min (Cockroft formula)
• Hematologic function allowing administration of CT: PNN> 1500, Pl> 100000, Hb> 9g
• Satisfactory Liver function: SGOT and SGPT <3N; total bilirubin <20 mg / dL; INR <1.5; albumin> 30 g / l
• Stomatological care adapted
• Signature of informed consent
• Bilateral neck irradiation Indication
• Women and men of reproductive age should have accepted a medically effective contraception during the treatment period and at least 6 months after discontinuation of study treatment. If pregnancy is declared by a patient or partner of a patient, it must be followed for know the evolution of pregnancy.

Exclusion Criteria:

• Cancers of the nasopharynx, sinus or nasal cavities
• Histology other than squamous
• Presence of distant metastases
• Prior systemic chemotherapy (neoadjuvant)
• Other concomitant cancer therapies
• Presence of infection requiring the use of IV antibiotics including tuberculosis and HIV infection
• Coronary insufficiency, cardiac arrhythmias, uncontrolled or symptomatic heart failure
• Uncontrolled hypertension
• Peripheral neuropathy grade> 1
• Vaccination against yellow fever and phenytoin recent or planned
• History of cancer within 5 years prior to trial entry other than cutaneous basal cell carcinoma in situ or cervical
• Pregnant woman capable of being or during lactation
• Persons deprived of liberty, under guardianship
• Inability to submit to medical monitoring testing for geographical, social or psychic
• Unilateral cervical radiotherapy Indication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Split Cisplatin and radiotherapy; 25 mg/m2/day IV infusion at D1 to D4, at D22 to D25, at D43 to D46 during the radiotherapy	Drug: Split Cisplatin; 25 mg/m2/day IV infusion at D1 to D4, at D22 to D25, at D43 to D46 during the radiotherapy.; Other Names: Cisplatin infusion; Radiation: Radiotherapy; 70 Gy in 35 fractions of 2 Gy in non-operated patients and 66 Gy in 33 fractions in post-operative.; Other Names: Radiotherapy IMRT with possibly integrated boost
Active Comparator: Cisplatin and radiotherapy; 100 mg/m2/day IV infusion at D1, D22 and D43 during the radiotherapy	Radiation: Radiotherapy; 70 Gy in 35 fractions of 2 Gy in non-operated patients and 66 Gy in 33 fractions in post-operative.; Other Names: Radiotherapy IMRT with possibly integrated boost; Drug: Cisplatin; 100 mg/m2/day IV infusion at D1, D22 and D43 during the radiotherapy.; Other Names: Cisplatin infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cumulative dose of administered cisplatin in each arm	cisplatin dose amount received at each cycle	36 months after the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of toxicities	Assessment of toxicity in accordance with NCI-CTC-AE 4.03	Every week during treatment and every 3 months after treatment up to 3 years
Maximum Platine Concentration [Cmax],	Blood sample	Cycle 1 before infusion, 90 min, 180 min,210 min, 270 min, 360 min and 420 min after the beginning of infusion in comparator arm and before infusion, 30 min, 45 min,75 min, 135 min, 225 min in experimental arm at Day 1 and Day 4
Area Under the Curve [AUC] of platine	Blood sample	Cycle 1 before infusion, 90 min, 180 min, 210 min, 270 min, 360 min and 420 min after the beginning of infusion in comparator arm and before infusion, 30 min, 45 min, 75 min, 135 min, 225 min in experimental arm at Day 1 and Day 4
Values of Neutrophil Gélatinase-associated Lipocalin (NGAL)	Urinary sample	Baseline and 24hour after infusion of cisplatin in comparator arm and 24hour after the last infusion of cisplatin in experimental arm
Doses of radiation	total dose received	7 weeks after the beginning of radiotherapy
Duration of radiation	Interruption of radiotherapy due to toxicity	7 weeks after the beginning of radiotherapy
Loco-regional failure rate	Delay between the date of randomisation and the occurrence of a recurrence	36 months after the end of randomization
overall survival	Delay between the date of randomization and death	36 months after the end of randomization

Collaborators and Investigators

• Sponsor: Groupe Oncologie Radiotherapie Tete et Cou
• Investigators: Principal Investigator: Christian BOREL, MD, Centre Paul Strauss

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2015
• Primary Completion (Actual): May 10, 2021
• Study Completion (Actual): May 10, 2021

Study Registration Dates

• First Submitted: January 17, 2017
• First Submitted That Met QC Criteria: November 1, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Actual): March 11, 2022
• Last Update Submitted That Met QC Criteria: March 10, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: GORTEC 2015-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes