The purpose of this study is to find an optimal smoking cessation strategy in patients undergoing therapy for lung and head and neck cancers at selected cancer centers in Kentucky by delivering high quality smoking cessation to all enrolled patients. This study will also examine the feasibility of routinely implementing an array of smoking cessation strategies for this patient population.

Subjects enrolled in the study will be placed in one of twelve treatment arms. Subjects in each of the twelve treatment regimens will receive either varenicline or bupropion or long-acting nicotine replacement therapy, with or without use of supplemental nicotine replacement therapy, and in combination with either standard of care smoking cessation counseling or high intensity/motivational smoking cessation counseling.

Inclusion Criteria:

• Patients must be ≥ 18 years of age.

• Patient with newly diagnosed or recurrent, histologic diagnosis of any of the following tobacco related malignancies:

  1. Lung or Bronchus cancer or Head & Neck, cancers (all sites).
  2. Esophagus, Stomach, Pancreas, Kidney, Urinary Bladder, Colon, Rectum, Cervix, Vulvar, Vaginal
  3. Carcinoma in situ undergoing definitive surgical resection or treatment (ex: radiation of the larynx, and gynecologic tract hysterectomy, vulvectomy - except gynecologic patients undergoing ablative or local excisional therapies [laser ablation,cervical conization, LEEP].

• Having smoked at least 1 cigarette within 4 weeks of study enrollment.

• Having at least a 10-pack year history of cigarette smoking.

• Having smoked at least one cigarette within 1 month of cancer diagnosis.

• Life expectancy is greater than 1 year.

• Patient has an AUDIT score of < 10.

• Patient has ECOG Performance Status of <=2.

• Patients must have the ability to understand and the willingness to provide signed written informed consent document.

Exclusion Criteria:

• Known allergy attributed to bupropion, varenicline, transdermal or lozenge nicotine.

• History of suicide attempt or preparation for attempt within the past 10 years.

• C-SRSS Baseline/Screening:

  1. Patient response of "Yes" to any question except question 1.
  2. Patient response of "Yes" to any question in column one (lifetime), except question 1, is not exclusionary unless judged by the investigator to be significant in ideation, intensity, behavior or attempts, and precludes participation.

• Hospitalized for psychiatric illness within the past two years.

• History of Bipolar disorder.

• Currently taking Bupropion for depression.

• Patient has taken monoamine oxidase inhibitors (MAOI) in the past two weeks.

• History of eating disorder such as anorexia or bulimia.

• Active widespread skin disorders such as psoriasis, chronic urticarial or dermatitis

• History of epilepsy or seizure disorder.

• Active severe kidney or liver disease.

• Women must not be pregnant or lactating. Women of reproductive-potential must have negative serum or urine pregnancy test within 7 days prior to study enrollment and agree to use method of contraception during and for 30 days following last cessation drug dose.

• Patients within three months of a myocardial infarction.

• Patients with unstable angina or serious arrhythmia.

• Patients with psychiatric disability judged by the investigator to be clinically significant so as to preclude informed consent or compliance with drug intake.

• Patient taking varenicline or bupropion within one month of study enrollment.

• Participation in any other investigational drug study within 4 weeks of study enrollment.

• Currently enrolled in other professional tobacco cessation therapeutic intervention.

• Enrollment in a concurrent cancer therapeutic trial will require prior review and approval by the study site PI to determine that there are no drug interactions concerns.