Dose-Escalated Hypofractionated Adaptive Radiotherapy for Head and Neck Cancer

Inclusion Criteria:

* Age ≥18 years
* Diagnosis of T3-T4 N0-N3 M0 or T0-T4 N1-N3 M0 squamous cell carcinoma of the head and neck squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary) based on American Joint Committee on Cancer guideline (AJCC; 8th edition) with measurable disease who meet at least 1 one of the following 3 criteria:

  1\. Not a candidates for concurrent, bolus, cisplatin-based chemoradiation therapy based on one of the following criteria (a-e)
  1. Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 4 week of registration:

     1. Modified Charlson Comorbidity Index ≥ 1
     2. Adult Comorbidity Evaluation-27 (ACE-27) Index ≥ 1
     3. ω score \< 0.80
     4. Geriatric 8 (G-8) score ≤ 14
     5. Cancer and Aging Research Group (CARG) Toxicity Score ≥ 30%
     6. Cumulative Illness Rating Scale-Geriatric (CIRS-G) Score ≥ 4
  2. Age \< 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 4 weeks prior to registration:

     1. Modified Charlson Comorbidity Index ≥ 1
     2. ACE-27 Index ≥ 1
     3. ω score \< 0.80
     4. G-8 score ≤ 14
     5. CARG Toxicity Score ≥ 30%
     6. CIRS-G Score ≥ 4
  3. Creatinine clearance \< 60 cc/min by the Cockroft-Gault formula
  4. Pre-existing peripheral neuropathy
  5. Clinical need for a hearing aid or 25+ decibel shift over 2 contiguous frequencies on a pre-treatment hearing test

     2\. Patient refuses concurrent cisplatin-based chemoradiation therapy

     3\. Patient has recurrent disease after definitive surgical resection
* Any patient 18 years or older with primary metastatic (AJCC 8th edition T1-T4 N0-N3 M1) squamous cell carcinoma of the head and neck
* Zubrod performance status 0-3
* Measurable primary and/or nodal tumor in the head and neck region at the time of radiotherapy
* Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.
* Ability to tolerate multiple MRIs
* Adequate hematologic function within 14 days prior to registration defined as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm\^3, platelets ≥ 100,000 cells/mm\^3, hemoglobin ≥ 9.0 g/dl, lymphocyte count ≥500/mL. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable).
* Adequate hepatic function within 14 days prior to registration defined as follows: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times institutional upper limit of normal, serum bilirubin ≤ 1.5 x institutional upper limit of normal.
* For patients not receiving therapeutic anticoagulation: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
* For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.
* Negative HIV test at screening{, with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral load}.
* Negative hepatitis B surface antigen (HBsAg) test at screening.
* Inclusion of Covid-19 positive patients will be based on standard institutional protocol.
* Female patients must meet one of the following:

  * Postmenopausal for at least one year before the screening visit, or
  * Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), or
  * If subject is of childbearing potential (defined as not satisfying either of the above two criteria), agree to practice two acceptable methods of contraception (combination methods require use of two of the following: diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge, male or female condom, hormonal contraceptive) from the time of signing of the informed consent form through 90 150 days after the last dose of study agent, AND o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, post ovulation methods\] and withdrawal are not acceptable contraception methods).
* Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following:

  * Practice effective barrier contraception during the entire study period and through 150 calendar days after the last dose of study agent, OR
  * Must also adhere to the guidelines of any study-specific pregnancy prevention program, if applicable, OR o Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptom-thermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.)
* Ability to understand a written informed consent document, and the willingness to sign it.

Exclusion Criteria:

* Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer);
* Life expectancy less than 12 months
* Performance status Zubrod \>3
* Inability to encompass all gross disease in 19 cm superior to inferior planning target volume to be treated on the MR LINAC
* MRI-incompatible foreign body
* Claustrophobia precluding ability to tolerate multiple MRIs
* MRI-incompatible pacemaker or implantable cardioverter defibrillator (ICD) placement
* Patients with Cochlear implant
* Patients with prior radiation therapy to the head and neck Note: Prior external beam radiotherapy is excluded, but Iodine 131 is allowed.
* Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer
* Major surgery within 28 days prior to registration
* Body weight ≤ 30 kg
* Any of the following severe laboratory abnormalities within 14 days of registration, unless corrected prior to it: Sodium \< 130 mmol/L or \> 155 mmol/L; Potassium \< 3.5 mmol/L or \> 6 mmol/L ;Fasting glucose \< 40 mg/dl or \> 400 mg/dl;Serum calcium (ionized or adjusted for albumin) \< 7 mg/dl or \> 12.5 mg/dl; Magnesium \< 0.9 mg/dl or \> 3 mg/dl
* Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to Step 1 registration
* Transmural myocardial infarction within 3 months prior to Step 1 registration
* Respiratory illness requiring hospitalization at the time of Step 1 registration
* Note: If the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial.
* Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to Step 1 registration
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Clinically apparent jaundice and/or known coagulation defects
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; Any chronic skin condition that does not require systemic therapy; Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair; Patients with celiac disease controlled by diet alone.
* History of active primary immunodeficiency including, but not limited to Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition. The need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive. Patients with known HIV, cluster of differentiation 4 (CD4) cell counts ≥ 200/μL, and undetectable viral loads who are stable on an antiretroviral regimen may be included.
* Current or prior use of immunosuppressive medication within 14 days before registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
* Receipt of live attenuated vaccination within 30 days prior to registration
* Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of atezolizumab, this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding are also excluded.
* Prior allergic reaction or hypersensitivity to atezolizumab or any of study drug excipients.
* History of allogenic stem cell or organ transplantation
* Uncontrolled hypertension
* Uncontrolled cardiac arrhythmia
* Uncontrolled serious chronic gastrointestinal condition associated with diarrhea
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice), hepatitis B (known positive hepatitis B viral (HBV) surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody (anti-HBc) and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* History of leptomeningeal disease.
* Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Patients with indwelling catheters (e.g., PleurXâ) are allowed.
* Uncontrolled or symptomatic hypercalcemia (ionized calcium \> 1.5 mmol/L, calcium \> 12 mg/dL or corrected serum calcium \> ULN)
* Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis

  * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
  * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
  * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    * Rash must cover \< 10% of body surface area
    * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
    * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
* Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
* Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

  o Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
* Live, attenuated vaccines (e.g., FluMistâ) are prohibited within 4 weeks prior to initiation of study treatment, during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab.
* Current treatment with anti-viral therapy for HBV
* Treatment with investigational therapy within 28 days prior to initiation of study treatment
* Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-Cytotoxic T lymphocyte-associated antigen (anti-CTLA-4), anti-PD-1, and anti-PD-L1 therapeutic antibodies.
* Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 (IL-2) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
* Known allergy or hypersensitivity to any component of the chemotherapy formulation
* Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of study treatment
* Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.