Intra-arterial Versus Intravenous Cisplatin, Combined With Radiation, for Oral Cavity and Oropharynx Cancer

Head and neck malignancies represent a group of epithelial tumors that arise from the oral
cavity, pharynx, and larynx and account for about 3 to 5% of all cancers in the United
States. In 2010, an estimated 49,260 people (35,530 men and 13,730 women) will develop head
and neck cancer, and an estimated 11,480 deaths (8,300 men and 3,180 women) will occur.

Three modalities of therapy have established roles in the treatment of carcinoma of the head
and neck: chemotherapy, radiation therapy, and surgery. The choice of modality depends upon
many factors such as the site and extent of the primary lesion, the likelihood of complete
surgical resection, the presence of lymph node metastases, etc. Traditionally, smaller
lesions (stage T1-T2) are effectively treated either, by surgical excision or irradiation
whereas more advanced disease (T3-T4) is treated with combined surgery and radiation or
chemoradiation. The goal of concurrent chemotherapy with radiation is to increase
locoregional control and prevent distant metastases.

A specific concomitant chemoradiation protocol for head and neck cancer known as RADPLAT
employs the pharmacologic principles and techniques described above. Capitalizing on the
cisplatin-neutralizing agent sodium thiosulfate and its pharmacokinetic properties, enormous
concentrations of cisplatin can be infused directly into large head and neck tumors through
a targeted IA approach. In a Phase I study, it was determined that cisplatin could be safely
administered to patients with advanced and recurrent head and neck cancer at a dose
intensity of 150mg/m2/week.

The patient must be considered a clinical candidate for either intra-arterial or intravenous
administration of cisplatin to be eligible for the study. Once enrolled and registered on
the study, the subject will be randomized to either intravenous or intra-arterial
administered cisplatin. Subjects will be assigned in a 1:1 ratio of intra-arterial versus
intravenous administration. All patients will receive concurrent radiation therapy. Standard
institutional practice will be applied for dose reduction and treatment of radiation therapy
related toxicities.

A combination of lateral opposing fields will be used for the treatment of the primary tumor
site and upper neck when three dimensional CRT is used and is not applicable for IMRT. A
single anterior A-P field can be used to treat the lower neck below the primary tumor/upper
neck. When there are positive nodes in the lower neck, an additional posterior field may be
necessary to deliver a supplemental dose to the positive nodes. All fields must be treated
on each treatment session.

The investigators will measure feasibility of the study protocol through enrollment and
screen failure data. The study will test the hypothesis that intra-arterial cisplatin is
more effective for patient outcomes in overall survival, disease free survival, cancer
specific survival, rate of local and regional control of cancer, site of recurrence, organ
preservation rate, toxicity, and correlative specimen availability.

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document

- Histologically or cytologically confirmed stage IV squamous cell carcinoma of the
oral cavity or oropharynx staged according to AJCC guidelines

- T4 staged tumor with a tumor volume greater than or equal to 30 cc

- Nodal staging of N0 through 2a

- No evidence of distant metastatic disease, as determined by a negative PET scan or
other clinically appropriate means

- Age ≥ 18

- Clinically eligible for both intra-arterial and intravenous administration of
cisplatin

- Women of childbearing potential must have a negative pregnancy test.

- Agree to use adequate contraception prior to study entry and for the duration of
study participation and for 3 months after study treatment ended

- Biopsiable via a transoral approach

- Life expectancy of at least 5 years

- ECOG performance status ≤ 2

- Measurable disease as defined by RECIST criteria

- Absolute neutrophil count ≥ 1,000/mm3

- Hemoglobin ≥ 8.0 g/dl

- Platelet count ≥ 100,000/mm3

- Leukocytes≥3500/mcL

- Total Bilirubin ≤ ULN of institution performing testing

- Creatinine within normal institutional limits

Exclusion Criteria:

- Radiologic evidence of bone destruction

- Tumor with involvement of cartilage or bone

- Requires bilateral IA infusion with radiologist determination that tumor extends
across the midline in excess of 30% of the tumor volume

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to agents and pre-medications used in the study, including drugs
formulated with polysorbate 80

- Allergy to cardiac catheterization contrast agents, in which antihistamines are not
sufficient to suppress a reaction or severe enough to pose a significant danger to
the subject

- History of stroke, CABG, or significant blockage of carotid arteries or coronary
arteries or current blockage of coronary or carotid arteries equal to or in excess of
50% blockage; Interventional radiology must agree that the patient is a good
candidate for catheterization.

- Intolerance to IV, IA, or radiation therapy treatment for any reason as determined by
the procedural physician

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnancy

- Breast feeding women

- Prior or concurrent non-head and neck malignancies, excluding adequately treated
basal or squamous cell cancer of the skin, in situ cervical cancer, stage I or II
cancer from which the subject has been in complete remission for at least 12 months,
any cancer from which the subject has been cancer free for 5 years

- Tumor site which cannot provide a biopsy in the clinic via punch or core needle
biopsy performed

- Second primary head and neck tumor (concurrent or previous head and neck tumor unless
it was a basal or squamous cell skin cancer)

- Unknown primary tumor site

- Prior surgery, chemotherapy, biologic or radiotherapy for a head or neck malignancy
(excluding minor surgical procedures for skin cancer)

- History of surgery (non-oncologic) in the field of the tumor or treatment bed.

- Participation in an investigational treatment or intervention study within 90 days of
screening visit

- calculated creatinine clearance less than 60 mL/min/1.73 m2