Rates of local disease control in patients with locally advanced esophageal cancer who are not candidates for surgical resection are suboptimal. Despite treatment with chemotherapy and radiation therapy approximately half of patients will develop recurrence of their cancer at the site of the original primary cancer. Salvage therapy options are largely ineffective and nearly all patients who develop local disease recurrence will succumb to their cancer. Recent clinical trials for lung cancer have demonstrated that local tumor control can be improved safely with accelerated hypofractionated radiation therapy regimens in order to achieve radiation dose intensification. This clinical trial aims to adapt those techniques and assess the safety of such a regimen for the treatment of inoperable thoracic esophageal cancers.

Inclusion Criteria:

• Biopsy-proven carcinoma of the thoracic esophagus, or gastroesophageal junction (GEJ).

• Amenable to definitive chemoradiation.

• Unresectable esophageal cancer or not a surgical candidate as determined by a surgeon or multidisciplinary tumor board.

• At least 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Complete blood count (CBC) with differential obtained within 30 days prior to registration with adequate bone marrow function:

  • Absolute neutrophil count (ANC) ≥1,500 cells/mm3
  • Platelets ≥100,000 cells/ mm3
  • Hemoglobin ≥9 g/dL (transfusion or other intervention to achieve hemoglobin ≥9 g/dL is acceptable).

• Adequate renal function within 30 days prior to registration: Serum creatinine ≤ 1.5x upper limit of normal or calculated creatinine clearance ≥ 50 mL/min within 30 days prior to registration estimated by the Cockcroft-Gault formula:

Creatinine Clearance (male) = [(140 - age) x (wt in kg)] [(Serum Creatinine mg/dl) x (72)] Creatinine Clearance (female) = 0.85 x Creatinine Clearance (male)

*Adequate hepatic function within 30 days prior to registration: bilirubin ≤ 1.5x upper limit of normal, ALT/AST ≤3 x upper limit of normal (ULN).

• Negative pregnancy test within 14 days of registration or otherwise be determined to not be of childbearing potential. Postmenopausal women must be amenorrheic for 12 months or more. Women of childbearing potential must agree to perform appropriate contraception methods and not breastfeed until 30 days after last chemotherapy.
• Planned to undergo IMRT with photon beam radiation therapy. 3D CRT and proton modalities are not allowed.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Primary cervical esophageal cancer

• Siewert-Stein Type III carcinomas of the stomach.

• Esophageal perforation, fistula, or deep ulceration to the mediastinum.

• Currently receiving any other investigational agents.

• Known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, paclitaxel, or other agents used in the study.

• Planning to undergo or has already undergone induction chemotherapy.

• Presence of any active malignancy within 2 years that may alter the course of esophageal cancer therapy.

• Prior radiation therapy to the neck, thorax, or abdomen is not allowed UNLESS there is expected to be no overlap with the study esophageal radiotherapy treatment. Prior radiation therapy treatment plan reports must be reviewed by study PI to verify no overlap of treatment fields.

• Severe active comorbidity as defined below:

  • Unstable angina and/or congestive heart failure within the last 6 months.
  • Transmural myocardial infarction within the last 6 months.
  • History of stroke, cerebral vascular accident, or transient ischemic attack within the last 6 months.
  • Serious and inadequately controlled cardiac arrhythmia
  • 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.
  • Peripheral neuropathy > grade 1 at time of registration.

• Persistent complications from any major surgery within 4 weeks of study treatment start.

• Any other major medical illness that in the investigator's opinion would prevent safe administration or completion of protocol therapy.

• Pregnant or lactating woman. Women of childbearing potential with positive pregnancy test at baseline, or women who have not taken a pregnancy test at baseline. A man or woman who does not agree to use appropriate contraception.

• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of AIDS-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective ART according to DHHS treatment guidelines is recommended.