Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-label, Randomized, Parallel-group, Multicenter Study of Neoadjuvant Docetaxel(Taxotere®) Plus Cisplatin Plus 5-fluorouracil Versus Neoadjuvant Cisplatin Plus 5-fluorouracil in Patients With Locally Advanced Inoperable Squamous Cell Carcinoma of the Head and Neck
Brief Summary: The Primary Objective is to evaluate the progression-free survival after treatment with docetaxel plus cisplatin plus 5-Fluorouracil (5-FU) (DCF) in comparison with cisplatin plus 5-FU (CF) in patient with locally advanced inoperable SCCHN The Secondary Objective is to evaluate and compare the clinical response rate both before and after radiotherapy, the local symptoms, the duration of response, the time to treatment failure, the survival, the toxicity and the quality of life in the 2 study groups.


Options:
A: Inclusion Criteria:

* Treatment naïve stage III (hypopharynx, or nasopharynx primary) or stage IVa/IVb (all sites) histologically proven SCCHN with no definitive evidence of metastatic disease
* Patients with unknown primary site of tumor and histologically proven squamous cell carcinoma of a cervical lymph node felt to arise from a site in the head and neck are eligible
* Patients must have at least one measurable site of disease according to RECIST criteria
* Age ≥ 18 years
* Karnofsky performance status \> 70%
* Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb \>9 g/dL
* Adequate liver function as shown by:
* Serum bilirubin ≤ 1.5 x ULN
* ALT and AST ≤ 2.5x ULN
* INR and PTT ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for \>2 weeks at time of randomization.)
* Adequate renal function: serum creatinine ≤ 1.5 x ULN
* Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
* Signed informed consent

Exclusion Criteria:

* Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
* Patients, who have had a major surgery \[defined as requiring general anesthesia but not including tonsillectomy, neck dissection, or panendoscopy (triple endoscopy or examination under general anesthesia)\], or significant traumatic injury within 4 weeks of start of study drug; patients who have not recovered from the side effects of any major surgery; or patients that may require major surgery during the course of the study
* Prior treatment with any investigational drug within the preceding 4 weeks
* Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
* Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
* Unequivocal demonstration of metastatic disease (i.e. M1 disease).
* Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
* Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
* Symptomatic congestive heart failure of New York heart Association Class III or IV
* Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
* Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
* Uncontrolled diabetes as defined by fasting serum glucose \>1.5 x ULN
* Active (acute or chronic) or uncontrolled severe infections
* Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
* A known history of HIV seropositivity
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
* Nota bene: subjects that require administration of everolimus through a feeding tube are allowed to participate
* Patients with an active, bleeding diathesis
* Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus)
* Patients who have received prior treatment with an mTOR inhibitor for SCCHN (sirolimus, temsirolimus, everolimus).
* Patients with a known hypersensitivity to everolimus (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
* Patients with a know hypersensitivity to cetuximab, cremaphor, paclitaxel, carboplatin, 5FU, hydroxyurea, or any compounds of similar chemical or biologic composition
* History of noncompliance to medical regimens
* Patients unwilling to or unable to comply with the protocol
* Baseline neurologic deficit (\> grade II neuropathy)
* Prior severe infusion reaction (grade 4) to a monoclonal antibody
B: Inclusion criteria:

* Tumor type: Histologically or cytologically proven squamous cell carcinoma of the head and neck (SCCHN) presenting with locally advanced disease at diagnosis. Primary tumor sites eligible are: oral cavity, oropharynx, hypopharynx and larynx.
* Extent of the disease:

  * Patients are required to have at least one measurable lesion.
  * Stage III or IV without evidence of distant metastases, according to the TNM staging system. Absence of metastases must be checked by chest X-ray (with or without Computed tomography (CT) ), abdominal ultrasound or CT in case of liver function test abnormalities, and bone scan in case of local symptoms.
  * Tumor considered as inoperable after evaluation by a multidisciplinary team. Reason for inoperability will be reported in the CRF
* World Health Organization (WHO) performance status 0 or 1
* Laboratory data:

  * Haematology:
* Neutrophil count \> or = 2.0\*10\^9/L
* Platelet count \> or = 100\*10\^9/L
* Hemoglobin \> or = 10 g/dl (6.2 mmol/L)

  * Hepatic function:
* Total serum bilirubin \< or = 1 time the upper normal limit (UNL) of the participating center
* Aspartate transaminase (ASAT/SGOT) and Alanine transaminase (ALAT/SGPT) \< or = 2.5UNL
* Alkaline phosphatase \< or = 5 UNL
* Patients with ASAT or ALAT \> 1.5UNL associated with alkaline phosphatase \>2.5UNL are not eligible for the study

  * Renal function:
* serum creatinine \< or = 120µmol/L (1.4 mg/dl) if values are \>120µmol/L, creatinine clearance should be \> or = 60 ml/min
* 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
* Patients informed consent form obtained

Exclusion criteria:

* Tumors of the nasopharynx, the nasal and paranasal cavities.
* Previous chemotherapy or radiotherapy for any reason and previous surgery for SCCHN at time of study entry.
* Prior treatment within a therapeutic clinical tria within 30 days prior to study entry
* Concurrent treatment with any other anticancer therapy
* Chronic treatment (\> or = 3 months) with corticosteroids at a daily dose \> or = 20mg methylprednisolone or equivalent.
* Concomitant use of drugs which could interact with 5-fluorouracil (e.g. cimetidine, allopurinol, folic or folinic acid, methotrexate and metronidazole)
* Previous or current malignancies at other sites with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin or other cancer curatively treated by surgery and with no evidence of disease for at least 5 years
* Symptomatic peripheral neuropathy \> or = grade 2 by NCIC-CTG criteria
* Clinical altered hearing
* Pregnant, lactating women or of childbearing potential unless adequate
* with other serious illness or medical condition including but not limited to:

  * unstable cardiac disease despite treatment
  * myocardial infarction within 6 months prior to study entry
  * history of significant neurologic or psychiatric disorders including dementia or seizures
  * active uncontrolled infection
  * active peptic ulcer
  * chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
C: Inclusion Criteria:

* Histologically proven, locally advanced stage III-IV A-B (UICC 2002) primary squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx, the supraglottic larynx
* Age ≥ 18
* Written informed consent for the participation in the clinical trial

Exclusion Criteria:

* Inadequate hepatic function: Bilirubin \> 2,0 mg/dl, SGOT, SGPT, AP, Gamma-GT \> 3 x ULN
* Inadequate bone marrow function: leukocytes \< 3,5 x 10\^9/l, platelets \< 100 x 10\^9/l or neutrophils \< 1,5 x 10\^9/l
* Serum creatinine \> 1,5 mg/dl, creatinine clearance \< 60ml/min
* Uncontrolled severe somatic or psychological disease: e.g. unstable angina pectoris; myocardial infarction during the last 6 months; significant cardial rhythm disorders; apoplexy; high grade stenosis of the carotis; neurological or psychiatric disorders including convulsive disorders; dementia; psychosis; active uncontrolled infection or sepsis; liver cirrhosis; Child stage B,C; severe liver function disorders; marginal changes in the blood count; severe kidney damage; HIV-infection
* Acute infections
* Fertile women without adequate contraception during and up to 6 months after therapy (the method of contraception has to be high effective as described in the Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95 mod) and it has to be discussed with the investigator)
* Pregnant or breast feeding women
* Men, who are not willing to use adequate contraception during and up to 6 months after therapy, that is discussed with the investigator
* ECOG-Status \> 1
* Reduced hearing function (especially higher frequencies)
* Exsiccosis
* Neuropathy, caused by cisplatin
* Concurrent malignancies, with exception of adequately treated basal cell carcinoma of the skin or in situ carcinoma or the cervix
* Prior radiotherapy of the neck or chemotherapy
* Distant metastasis
* Recurrent carcinoma in the head and neck region
* Prior neck-dissection or surgical intervention exceeding an exploratory excision
* Known intolerance to 5-Fluorouracil
* Known deficit of Dihydropyrimidine dehydrogenase (DPD)
* Simultaneous therapy with Brivudin or other inhibitors of DPD
* Known intolerance to Cisplatin or other substances that contain platin
* Known intolerance to Paclitaxel or one of the included substances, especially to Poly(oxyethylene)Rhizinusöl/Macrogolglycerol ricinoleate
D: Inclusion Criteria:

1. Histologically or cytologically proven squamous cell carcinoma of the head and neck.
2. Primary tumor sites eligible : oral cavity, oropharynx, hypopharynx Although they are admittedly of squamous cell types, the following tumors will be excluded because of them responsiveness to chemotherapy: tumors of the nasal and paranasal cavities and of the nasopharynx.
3. Stage 3 or 4 disease without evidence of distant metastases verified by chest X Ray, abdominal ultrasound, or CT (liver function test abnormalities); bone scan in case of local symptoms.
4. At least one uni or bidimensionally measurable lesion.
5. Tumor considered inoperable after evaluation by a multidisciplinary team (i.e. a surgeon, a medical oncologist and a radiation oncologist). Criteria for inoperability are:

   1. technical unresectability: tumor fixation/invasion to base of the skull or cervical vertebrae, involvement of the nasopharynx, and fixed lymph nodes.
   2. Physician decision based on low surgical curability. This category will include the following:

   i) All T3-4 stages. ii) All N2-3 stages excluding T1 N2. iii) Patients for organ preservation. Reason for inoperability will be recorded in the CRF.
6. No previous chemotherapy or radiotherapy for any reason and no previous surgery for SCCHN (other than biopsy) are allowed at time of study entry.
7. Age \> 18 years.
8. Karnofsky performance status \> 70. (ECOG 0-1) (Appendix II)
9. No active alcohol addiction.
10. Life expectancy \> 6 months.
11. Signed informed consent prior to beginning protocol specific procedures.
12. Adequate bone marrow, hepatic and renal functions as evidenced by the following:

    a) Hematology (Bone marrow): i) Neutrophils \> 2.0 109/L ii) Platelets \> 100 x 109/L iii) Hemoglobin \> 10 g/dL b) Hepatic function i) Total bilirubin \< 1 x UNL ii) ASAT (SGOT) and ALAT (SGPT) \< 2.5 x ULN iii) Alkaline phosphatase \< 5 x ULN Patients with ASAT or ALAT \> 1.5 x ULN associated with alkaline phosphatase \> 2.5 x ULN are not eligible for the study.

    c) Renal function : serum creatinine \< 1 x UNL. In case of borderline value the creatinine clearance \> 60 ml/min (calculated by the Cockcroft-Gault method as follows :
13. Patients must be available for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating center.

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Exclusion Criteria:

1. Pregnant or lactating women or women of childbearing potential not using adequate contraception.
2. Previous or current malignancies at other sites, with the exception of adequately treated in situ carcinoma of the cervix uteri, basal or squamous cell carcinoma of the skin, or other cancer curatively treated by surgery and with no evidence of disease for at least 5 years. Any prior treatment with radiotherapy or chemotherapy is an exclusion criterion.
3. Symptomatic peripheral neuropathy \> grade 2 by NCIC-CTG criteria
4. Symptomatic altered hearing \> grade 2 by NCIC-CTG criteria.
5. Other serious illnesses or medical conditions including:

   1. Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry.
   2. History of significant neurologic or psychiatric disorders including dementia or seizures.
   3. Active uncontrolled infection.
   4. Active peptic ulcer.
   5. Hypercalcemia.
   6. Chronic obstructive pulmonary disease requiring hospitalization during the year preceding study entry
6. History of hypersensitivity reaction to polysorbate 80 (Appendix IV)
7. Patients requiring intravenous alimentation.
8. Patients who experienced a weight loss of more than 20% of their body weight in the 3 months preceding study entry.
9. Concomitant treatment with any other anticancer therapy.
10. Participation in a therapeutic clinical trial within 30 days of study entry

Answer: B