Head and Neck Cancer
Conditions
Keywords
stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx, tongue cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as docetaxel, cisplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with cetuximab may kill more tumor cells. PURPOSE: This phase II clinical trial is studying how well cetuximab given together with combination chemotherapy works in treating patients with stage III or stage IV oropharynx cancer that can be removed by surgery.
Detailed description
OBJECTIVES: Primary * To determine the complete clinical response rate at 3 months in patients with stage III or IV nonmetastatic squamous cell carcinoma of the oropharynx treated with cetuximab, docetaxel, cisplatin, and fluorouracil. Secondary * To determine the rate of tumor response. * To determine progression-free and overall survival. * To determine the rate of complete pathological response. * To assess the tolerability of this regimen in these patients. OUTLINE: This is a multicenter study. Patients receive cetuximab IV over 1-2 hours on days 1, 8, and 15; docetaxel IV over 1 hour and cisplatin IV over 1 hour on day 1; and fluorouracil IV continuously on days 1-5. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 2 months for 1 year and every 3 months for 2 years.
Interventions
DRUGcisplatin
75 mg/m², day 1. 3 cycles
DRUGdocetaxel
75 mg/m² Day 1. 3 cycles
DRUGfluorouracil
750 mg/m² day 1 to day 5. 3 cycles
DRUGCetuximab
400 mg/m² Day 1, 250 mg/m² Day 8 and Day 15. 3 cycles.
Sponsors
GERCOR - Multidisciplinary Oncology Cooperative Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed squamous cell carcinoma of the oropharynx * Stage III (T3 or T1-2, N1-2, M0) or nonmetastatic stage IV (T4 or T1-3, N3, M0) disease * Resectable disease * Measurable or evaluable disease * Tumor tissue available PATIENT CHARACTERISTICS: Inclusion criteria: * WHO performance status 0-1 * ANC ≥ 1,500/mm3 * Platelet count ≥ 100,000/mm3 * Hemoglobin ≥ 9 g/dL * Creatinine \< 1.5 times upper limit of normal (ULN) * Creatinine clearance ≥ 60 mL/min * AST and ALT \< 5 times ULN * Bilirubin \< 1.5 times ULN * Not pregnant or nursing * Fertile patients must use effective contraception * Affiliated with social security (including CMU)
Exclusion criteria
* Cardiovascular accident (myocardial infarction, cerebral vascular accident) within the past 6 months * Serious and/or uncontrolled cardiac or respiratory disease (pulmonary fibrosis, interstitial pneumopathy) * Other cancer within the past 5 years except for resected skin cancer, localized cutaneous or totally resected melanoma, or resected carcinoma in situ of the cervix * Auditory condition precluding the use of cisplatin * Contraindication due to psychological, social, or geographical reasons that may impede proper monitoring of treatment * Persons under guardianship or trusteeship, or prisoners of law PRIOR CONCURRENT THERAPY: * No prior treatment, including chemotherapy or radiotherapy * No concurrent phenytoin, live attenuated vaccines, or parenteral aminoglycosides
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and Radiological Complete Clinical Response (crCR) Rate at 3 Months | at 3 months after ETPF combination | The evaluation of tumor response rate was assessed by computed tomography scan of the neck and chest at Baseline, then at 3 months from inclusion using RECIST1.0 criteria and clinical examination |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Clinical Response (cCR) | at 3 months | Clinical complete response (cCR) is defined by: * Disappearance of all clinical evidence of visible tumor, * Disappearance of all palpable residual infiltration, * Disappearance of all evidence of residual visible tumor on CT scan in pharynx and parapharyngeal space, * Complete symmetric remobilization of the tongue and amygdala. * Disappearance of pre-existing trismus. * Negative control biopsy. The evaluation of tumor response rate was assessed by computed tomography scan of the neck and chest at Baseline, then at 3 months from inclusion using RECIST1.0 criteria and clinical examination |
| The 2-year Estimated Overall Survival (OS) Rate | 2 years | 2-year OS measured survival at 2 years from randomization. |
| The 2-year Estimated Progression-free Survival (PFS) | 2 years | 2-year PFS measured survival at 2 years from randomization. |
| Complete Radiological Response (rCR) | At 3 months after the end of 3 cycles of the ETPF combination | Radiological response is defined according to RECIST 1.0 criteria: * Complete response (CR): disappearance of all target lesions * Partial response (PR): at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, * Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of target the appearance of one or more new lesions, * Stable disease (SD): neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started |
| Pathologic Response | after surgery of the primary tumor | On primary tumor resected : measure of persistence or not of tumoral lesion, histological type, size and quality of the excision piece A pathological complete response is defined as no viable tumour cells detected on histological examination post surgery. |
Other
| Measure | Time frame |
|---|---|
| Biomarkers Analysis - HPV Genotyping | correlative studies investigating HPV status in tumor and blood samples obtained prior to and after induction therapy were done for exploratory purposes as planned in the protocol |
Countries
France
Participant flow
Recruitment details
From July 2008 to April 2013, 42 patients were enrolled. This study was conducted in France, in 9 active centers: Hospital Tenon, HEGP, Hospital Bichat, GH St Joseph Paris, Hospital Foch Suresnes, CH Lyon Sud, Hospital Delafontaine St Denis, Centre René Huguenin St Cloud et Hospital Simone Veil Montmorency.
Pre-assignment details
The main inclusion criteria: Previously untreated, resectable stage III (T3 or T1 - 2N1 - 2M0) to IVB (T4 or T1 -3N3M0) SCCHN of the oropharynx, measurable or evaluable disease, WHO performance status ≤ 1, adequate hematologic, renal and liver functions. The main exclusion criteria: uncontrolled cardiac or other disease, hearing impairment
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab cisplatin: 75 mg/m², day 1. 3 cycles
docetaxel: 75 mg/m² Day 1. 3 cycles
fluorouracil: 750 mg/m² day 1 to day 5. 3 cycles
Cetuximab: 400 mg/m² Day 1, 250 mg/m² Day 8 and Day 15. 3 cycles. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | not treated | 1 |
Baseline characteristics
| Characteristic | Cetuximab |
|---|---|
| Age, Continuous | 56.1 years STANDARD_DEVIATION 6.8 |
| Albuminemia (g/L) < 40 | 8 participants |
| Albuminemia (g/L) ≥ 60 | 14 participants |
| Albuminemia (g/L) Missing | 20 participants |
| Cancer Staging at the inclusion III | 32 participants |
| Cancer Staging at the inclusion IV | 10 participants |
| Creatinine clearance (mL/min) > 120 | 8 participants |
| Creatinine clearance (mL/min) < 60 | 1 participants |
| Creatinine clearance (mL/min) 60 -120 | 31 participants |
| Creatinine clearance (mL/min) Missing | 2 participants |
| ECOG performance status ECOG - PS=0 | 33 participants |
| ECOG performance status ECOG - PS=1 | 8 participants |
| ECOG performance status Missing | 1 participants |
| Grade of differentiation Missing | 3 participants |
| Grade of differentiation Moderate | 18 participants |
| Grade of differentiation Poor or undifferentiated | 4 participants |
| Grade of differentiation Well | 17 participants |
| HPV 16 status Negative | 25 participants |
| HPV 16 status Positive | 17 participants |
| Life style risk factors Alcohol | 3 participants |
| Life style risk factors Alcohol + Tobacco | 25 participants |
| Life style risk factors None | 6 participants |
| Life style risk factors Tobacco | 8 participants |
| Lip mobility Decreased | 2 participants |
| Lip mobility Normal | 40 participants |
| N-stage N0 | 5 participants |
| N-stage N1 | 9 participants |
| N-stage N2 | 27 participants |
| N-stage N3 | 1 participants |
| Primary tumor localization Anterior | 3 participants |
| Primary tumor localization Lateral (tonsillar area) | 37 participants |
| Primary tumor localization Posterior | 1 participants |
| Primary tumor localization Superior | 1 participants |
| Region of Enrollment France | 42 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 34 Participants |
| Trismus No | 37 participants |
| Trismus Yes | 5 participants |
| T-stage T2 | 13 participants |
| T-stage T3 | 24 participants |
| T-stage T4 | 5 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 13 / 41 |
Outcome results
Primary
Clinical and Radiological Complete Clinical Response (crCR) Rate at 3 Months
The evaluation of tumor response rate was assessed by computed tomography scan of the neck and chest at Baseline, then at 3 months from inclusion using RECIST1.0 criteria and clinical examination
Time frame: at 3 months after ETPF combination
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETPF Administration | Clinical and Radiological Complete Clinical Response (crCR) Rate at 3 Months | Tumor response Rate - Tumor | 9 participants |
| ETPF Administration | Clinical and Radiological Complete Clinical Response (crCR) Rate at 3 Months | Tumor response rate - node | 8 participants |
| ETPF Administration | Clinical and Radiological Complete Clinical Response (crCR) Rate at 3 Months | Tumor response rate - Tumor and node | 4 participants |
Secondary
Complete Clinical Response (cCR)
Clinical complete response (cCR) is defined by: * Disappearance of all clinical evidence of visible tumor, * Disappearance of all palpable residual infiltration, * Disappearance of all evidence of residual visible tumor on CT scan in pharynx and parapharyngeal space, * Complete symmetric remobilization of the tongue and amygdala. * Disappearance of pre-existing trismus. * Negative control biopsy. The evaluation of tumor response rate was assessed by computed tomography scan of the neck and chest at Baseline, then at 3 months from inclusion using RECIST1.0 criteria and clinical examination
Time frame: at 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETPF Administration | Complete Clinical Response (cCR) | Tumor response rate - tumor | 17 participants |
| ETPF Administration | Complete Clinical Response (cCR) | Tumor response rate - node | 15 participants |
| ETPF Administration | Complete Clinical Response (cCR) | Tumor response rate - Tumor and node | 13 participants |
Secondary
Complete Radiological Response (rCR)
Radiological response is defined according to RECIST 1.0 criteria: * Complete response (CR): disappearance of all target lesions * Partial response (PR): at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, * Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of target the appearance of one or more new lesions, * Stable disease (SD): neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started
Time frame: At 3 months after the end of 3 cycles of the ETPF combination
Population: Patients in the mITT population who received ETPF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETPF Administration | Complete Radiological Response (rCR) | Tumor response rate - Tumor | 14 participants |
| ETPF Administration | Complete Radiological Response (rCR) | Tumor response rate - Node | 8 participants |
| ETPF Administration | Complete Radiological Response (rCR) | Tumor response rate - Tumor and node | 4 participants |
Secondary
Pathologic Response
On primary tumor resected : measure of persistence or not of tumoral lesion, histological type, size and quality of the excision piece A pathological complete response is defined as no viable tumour cells detected on histological examination post surgery.
Time frame: after surgery of the primary tumor
Population: Pathological response is evaluable in patients with tumor surgical resection only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ETPF Administration | Pathologic Response | 9 participants |
Secondary
The 2-year Estimated Overall Survival (OS) Rate
2-year OS measured survival at 2 years from randomization.
Time frame: 2 years
Population: Median OS was not achieved. The 2-year estimated rate is given.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ETPF Administration | The 2-year Estimated Overall Survival (OS) Rate | 82 percentage of participants |
Secondary
The 2-year Estimated Progression-free Survival (PFS)
2-year PFS measured survival at 2 years from randomization.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ETPF Administration | The 2-year Estimated Progression-free Survival (PFS) | 64 percentage of participants |
Other Pre-specified
Biomarkers Analysis - HPV Genotyping
Time frame: correlative studies investigating HPV status in tumor and blood samples obtained prior to and after induction therapy were done for exploratory purposes as planned in the protocol
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ETPF Administration | Biomarkers Analysis - HPV Genotyping | HPV16 - Positive | 17 participants |
| ETPF Administration | Biomarkers Analysis - HPV Genotyping | HPV16 - Negative | 25 participants |