Radiation Therapy with or without Chemotherapy in Treating Patients with High-Risk Malignant Salivary Gland Tumors That Have Been Removed by Surgery

This randomized phase II / III trial studies radiation therapy with or without chemotherapy to see how well it works in treating patients with high-risk malignant salivary gland tumors that have been removed by surgery. Radiation therapy uses high-energy x-rays or protons to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether radiation therapy is more effective when given together with chemotherapy or alone after surgery in treating salivary gland tumors.

Inclusion Criteria

• Pathologically proven diagnosis of a malignant major salivary gland tumor or malignant minor salivary gland tumor of the head and neck of the following histologic subtypes: * Intermediate-grade adenocarcinoma or intermediate-grade mucoepidermoid carcinoma * High-grade adenocarcinoma or high-grade mucoepidermoid carcinoma or salivary duct carcinoma * High-grade acinic cell carcinoma or high-grade (> 30% solid component) adenoid cystic carcinoma * Patients with diagnoses such as "undifferentiated or poorly differentiated carcinoma", "carcinoma-ex pleomorphic adenoma", "carcinoma not otherwise specified (NOS)" and others should be considered for this trial
• Surgical resection with curative intent within 8 weeks prior to registration
• Pathologic stage T3-4 or N1-3 or T1-2, N0 with a close (=< 1 mm) or microscopically positive surgical margin (American Joint Committee on Cancer [AJCC], 7th edition); patients must be free of distant metastases based upon the following minimum diagnostic workup: * History/physical examination within 8 weeks prior to registration * Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to registration; at a minimum, contrast computed tomography (CT) imaging of the chest is required; positron emission tomography (PET)/CT is acceptable
• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) >= 1,800 cells/mm^3 (within 8 weeks prior to registration)
• Platelets >= 100,000 cells/mm^3 (within 8 weeks prior to registration)
• Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) (within 8 weeks prior to registration)
• Serum creatinine < 2.0 mg/dl (within 8 weeks prior to registration)
• Total bilirubin < 2 x the institutional upper limit of normal (ULN) (within 8 weeks prior to registration)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the institutional ULN (within 8 weeks prior to registration)
• Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential
• Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment and for 6 weeks following treatment
• All patients must have a Medical Oncology evaluation within 4 weeks prior to registration
• Patients must be deemed able to comply with the treatment plan and follow-up schedule
• Patients must provide study specific informed consent prior to study entry, including consent for mandatory tissue submission for central review

Exclusion Criteria

• Patients with residual macroscopic disease after surgery
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Prior systemic chemotherapy or radiation therapy for salivary gland malignancy; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, coagulation parameters are not required for entry into this protocol * Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol * Pre-existing >= grade 2 neuropathy * Prior organ transplant
• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
• Significant pre-existing hearing loss, as defined by the patient or treating physician

PRIMARY OBJECTIVES:

I. Determine the feasibility of conducting a cooperative group prospective clinical trial in patients with resected malignant salivary gland tumors. (Phase II)

II. Acquire preliminary efficacy data comparing postoperative radiotherapy alone to concurrent chemotherapy and radiation using weekly cisplatin. (Phase II)

III. Compare overall survival rates among patients receiving cisplatin and radiation to those receiving radiation alone. (Phase III)

SECONDARY OBJECTIVES:

I. Compare the acute toxicities of these 2 adjuvant treatments.

II. Compare late treatment-related adverse events in patients receiving postoperative radiation to those receiving concurrent chemoradiation.

III. Compare progression-free survival rates among patients receiving cisplatin and radiation to those receiving radiation alone in both the cohort of patients with pathologically high-risk disease (high-grade adenocarcinoma, high-grade mucoepidermoid carcinoma, salivary duct carcinoma), and the patient cohort with pathologically intermediate-risk disease (all other eligible diagnoses).

IV. Investigate quality of life and patient-reported outcomes in patients enrolled in the study.

V. Identify the histopathology and tumor marker expression from patients enrolled on this trial and assemble a tissue bank for future correlative studies.

VI. Establish an NRG Oncology baseline database for salivary gland malignancies to serve as a resource for future exploration of innovative and/or targeted approaches for this disease.

OUTLINE: Patients are stratified according to histology (intermediate-grade adenocarcinoma or intermediate-grade mucoepidermoid carcinoma vs high-grade adenocarcinoma, high-grade mucoepidermoid carcinoma or salivary duct carcinoma vs high-grade acinic cell carcinoma or high-grade [> 30% solid component] adenoid cystic carcinoma), nodal status (N0 vs N1-3), and type of radiation (photon vs proton). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients undergo 3-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or intensity modulated proton therapy (IMPT) 5 days a week for 6 or 6.5 weeks. Patients also receive cisplatin intravenously (IV) over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiotherapy.

Arm II: Patients undergo 3D-CRT, IMRT, or IMPT as in Arm I.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, and 24 months, every 6 months for 2 years, and then annually thereafter.

Lead Organization
NRG Oncology

Principal Investigator
Cristina Paguia Rodriguez