The purpose of this study is to determine whether human papillomavirus (HPV)-positive head and neck cancer can be treated with a less aggressive regimen of radiation therapy and chemotherapy (paclitaxel) after initially receiving two cycles of chemotherapy (carboplatin/paclitaxel).

Given the toxicity of high dose cisplatin, attention has focused on identifying patients at lower risk for failure who may potentially benefit from less aggressive chemoradiotherapy approaches. HPV-positive Head and Neck Cancer responds favorably to radiation therapy. This has prompted investigators to suggest that patients with these cancers might be "over-treated" and unnecessarily subjected to the toxicity of intensive chemoradiotherapy with excessively high radiation doses.

This study will select patients with HPV-positive Head and Neck cancer for attenuated therapy and may have important implications for individualization of care in the future. The regimen of carboplatin and paclitaxel was selected for the induction chemotherapy phase because of its ease of administration, improved toxicity profile, high rates of dose delivery, and excellent published results showing high response rates and overall survival. This study will use induction chemotherapy primarily as a means to select HPV-positive Head and Neck Cancer patients, who may benefit from significant radiation dose de-intensification in the concurrent chemoradiotherapy phase of treatment. The rationale for this risk-adapted approach to local therapy based on HPV status is to administer effective comprehensive treatment individualized at diagnosis and after assessment of response to induction chemotherapy (for patients with HPV-positive tumors), thus avoiding unnecessary and potentially toxic treatment, and hence optimizing the therapeutic ratio.

Inclusion Criteria:

• Pathologically proven diagnosis of HPV-positive squamous cell carcinoma of the oropharynx, hypopharynx, or larynx. HPV-positivity will be defined as tumors that are p16-positive by immunohistochemistry.
• Clinical stage III or IV disease; Note: Patients with M1 tumors are not eligible.
• Appropriate stage for protocol entry, including no distant metastases, based upon minimum diagnostic workup
• Zubrod Performance Status 0-1
• Age > 18
• Adequate bone marrow function
• Adequate hepatic function
• Adequate renal function
• Pregnancy test within 4 weeks prior to registration for women of childbearing potential
• Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study (until at least 60 days following the last study treatment)
• Patient must sign study specific informed consent prior to study entry.

Exclusion Criteria:

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years;
• Patients with simultaneous primaries or bilateral tumors are excluded.
• Patients who present with a cervical lymph node metastasis of unknown primary origin;
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable;
• Prior radiotherapy that would result in overlap of radiation therapy fields;
• Primary site of tumor of oral cavity, nasopharynx, nasal cavity, paranasal sinuses, or salivary glands;
• Recurrent head and neck cancer;
• Severe, active co-morbidity
• Pregnant or lactating women or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
• Prior allergic reaction to the study drug(s) involved in this protocol.

5 years