Taking into account the excellent prognosis of patients with HPV-positive oropharyngeal cancer with < 10 pack-year smoking, the investigators hypothesize that reducing the intensity of therapy for these patients will reduce treatment sequelae, notably long-term dysphagia, without affecting their cure rates. The main Aim is to assess whether reducing treatment intensity, by replacing concurrent chemotherapy with cetuximab, will indeed achieve improved long-term toxicity.

The primary objectives include the following: to confirm that reducing treatment intensity in patients with HPV-related oropharyngeal cancer and < 10 pack-year smoking history by replacing concurrent chemotherapy with concurrent cetuximab, does not significantly increase the proportion of patients whose tumors recur, compared to our previous experience in similar patients receiving chemo-RT and to compare the toxicity in patients receiving cetuximab-RT to similar patients treated with 7 weeks of chemotherapy concurrent with RT ("standard therapy") in UMCC 2-21.

The investigators have shown in past experience a high success in getting rid of oropharyngeal cancer (tonsil or base of tongue cancer) using chemotherapy and radiation therapy in patients who have not smoked, or only smoked a minimal amount of cigarettes or equivalent. In these patients, the cancer is thought to be caused by a virus (Human Papilloma Virus, or HPV). HPV is a virus that infects the epidermis (outermost layer of skin) and mucous membranes of humans. In general, patients with HPV-related cancer such as yours have a better prognosis compared with patients whose tumors are smoking-related. Taking into account the good prognosis, it is possible that reducing the intensity of therapy will not affect the high rate of tumor control, while reducing the side-effects of therapy. In this study, the investigators plan to reduce the intensity of treatment by replacing the currently used chemotherapy drugs with an FDA approved drug, cetuximab, which is a monoclonal antibody to a growth factor which helps cancer cells grow. By opposing the effect of the growth factor, cetuximab may help radiotherapy kill cancer cells without a lot of effect on the normal tissue. It differs from chemotherapy in its more selective activity against tumors compared to normal tissue Cetuximab has the chance to preserve the high rate of success in killing the tumor but may reduce the side effects and complications of therapy in comparison to chemotherapy drugs.

The investigators would also like to know if taking cetuximab has any effect on certain cancer-related molecules in the cancer and the normal cells inside the cheek. They would like to test this by taking a small biopsy of the tumor, as well as a swab of the inside of the cheek, before and shortly after the start of therapy.

Inclusion Criteria:

• Patients must have pathologically-confirmed, previously untreated,stage III-IV(excluding N3 or T4) squamous cell carcinoma of the oropharynx, without evidence of distant metastasis
• Pretreatment tumor biopsy with sufficient tumor for HPV or p16 analysis is required. The tumor must be HPV(+) or p16(+)

Smoking history <10 pack-year or equivalent (including cigarettes, cigars, pipes, chewing tobacco, and/or marijuana). One cannabis joint is equivalent to 5 cigarettes. (Aldington etal, Thorax 2007; 62:1058-1063). Smoking status definitions (National Health Interview Survey and Behavioral Risk Factor Surveillance System (Nelson DE etal al, Am J Pub Health 2003;93:1335):

• Smokers: smoking now every day or some days in past month

• Quitters: at least 100 cigarettes/lifetime and not smoking in the past 1-12 months

• Former smoker: at least 100 cigarettes/lifetime and not smoking >12 months

• Never smokers: <100 cigarettes (or equivalent)/lifetime

  • KPS > 80 (see Appendix A)
  • Patients must undergo pre-treatment endoscopic tumor staging and PET-CT scanning
  • Laboratory criteria:

• WBC > 3500/ul

• granulocyte > 1500/ul

• Platelet count > 100,000/ul

• Total Bilirubin < 1.5 X ULN

• AST and ALT < 2.5 X ULN

  • Creatinine clearance >30 cc/min
  • Patients must sign study specific informed consent
  • Patients must have, in the opinion of a treating physician, tumor that is accessible to biopsy in the clinic.

Exclusion Criteria:

• Prior head and neck malignancy or history of other prior non-head and neck malignancy (excluding skin cancer and early stage treated prostate cancer) within the past 3 years
• Prior head and neck radiation or chemotherapy
• Any medical or psychiatric illness, which in the opinion of the principal investigator, would compromise the patient's ability to tolerate this treatment or limit compliance with study requirements
• Patients residing in prison
• Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody or small molecule)

3 years