Induction Chemotherapy Response-Guided Radiation for EBV-Associated Nasopharyngeal Carcinoma

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed (from primary lesion and/or lymph nodes) nasopharyngeal carcinoma.
* Participants must have Epstein Barr virus (EBV)-associated nasopharyngeal carcinoma, defined as detectable (\> 0 copies/mL) circulating plasma EBV DNA on a qualitative or quantitative polymerase chain reaction (PCR)-based test.
* Stage III-IVA disease (American Joint Committee on Cancer \[AJCC\], 8th edition \[ed.\]) with no evidence of distant metastasis at the time of diagnosis based upon all 3 of the following minimum diagnostic workup criteria:

  * History/physical examination by a medical oncologist or clinical oncologist or radiation oncologist or otolaryngology (ENT);
  * Evaluation of tumor extent with either one of the following:

    * MRI with contrast of the face, nasopharynx, and neck or CT with contrast of the face, nasopharynx and neck with ≤ 3 mm contiguous slices and bone windows to evaluate base of skull involvement; or
    * MRI of the nasopharynx and PET/CT (with contrast) of the neck
  * Imaging to rule out distant metastasis:

    * CT scan with contrast of the chest and abdomen (required) and the pelvis (optional) or a total body PET/CT scan (non-contrast PET/CT is acceptable); and
    * Only if clinically indicated: Bone scan only when there is suspicion of bone metastases (a PET/CT scan can substitute for the bone scan)
* Started or planning to start platinum-based induction systemic therapy.
* Planning to receive intensity modulated radiation therapy (IMRT) with concurrent, platinum-based systemic therapy during radiation.
* Use of adjuvant (post-chemoradiation) immunotherapy is permitted.
* Age \>=18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 50%).
* Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy are eligible for this trial.
* For individuals with evidence of chronic hepatitis B virus (HBV) infection: must be on suppressive therapy, if indicated.
* For individuals with a history of hepatitis C virus (HCV) infection: must be currently on treatment, or must have been treated and cured.
* Individuals with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Because the radiation therapy used in this trial is known to be teratogenic, individuals of reproductive potential must agree to use adequate contraception (e.g., hormonal or barrier methods, abstinence) for the duration of study participation and for at least 60 days after the last administration of radiation therapy. Should a study participant or their partner become pregnant or suspect pregnancy while participating in this study, they should inform their treating physician immediately.
* Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

* Prior systemic chemotherapy for nasopharyngeal carcinoma, other than induction chemotherapy (IT); note that prior chemotherapy for a different cancer is permitted
* Prior radiotherapy to the nasopharynx or surrounding involved areas that would result in overlap of radiation therapy fields
* Has participated in a study of an investigational product and received treatment with an investigational drug or used an investigational device within 4 weeks prior to the first dose of treatment
* Severe, active comorbidity, defined as any of the following:

  * Major medical or psychiatric illness that, in the treating investigator's opinion, would interfere with the completion of therapy and follow-up or interfere with a full understanding of the risks and potential complications of the therapy
  * Unstable angina, congestive heart failure, or peripheral vascular disease requiring hospitalization within the last 12 months; or other cardiac compromise that in the judgment of the treating investigator will preclude safe administration of study treatment
  * Chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization within 30 days prior to registration, or which would preclude safe administration study therapy in the opinion of the treating investigator
  * Active, untreated infection and/or acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
* Because the radiation therapy used in this trial is known to be teratogenic, individuals of child-bearing potential must have documentation in their medical record of a negative pregnancy test

  \* A female participant is considered to NOT be of child-bearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice), if the participant meets either of the following two criteria:
  * Has reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause)
  * Has undergone surgical sterilization (i.e., hysterectomy and/or bilateral oophorectomy for removal of uterus and/or ovaries)
* Individuals with any condition or social circumstance that, in the opinion of the investigator, would impair the participant's ability to comply with study activities or interfere with participant safety or study endpoints