Induction FLOT with CROSS CRT for Esophageal Cancer

Inclusion Criteria:

1. Provision to sign and date the consent form.

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

3. Be a male or female aged 18-100.

4. Have newly diagnosed, resectable cT3-T4 or node positive adenocarcinoma of theesophagus or gastroesophageal junction as assessed by CT or MRI of the chest,abdomen and pelvis and by endoscopic ultrasound, with pathologic diagnosis obtainedwithin 3 months of signing consent, without delivery of prior chemotherapy orradiation therapy.

5. Subjects must be previously untreated with systemic chemotherapy or radiationtherapy.

6. Subjects must be deemed a candidate for trimodality therapy (radiation, chemotherapyand surgery) based upon multidisciplinary evaluation with plan for preoperativechemoradiation followed by surgical resection.

7. ECOG performance status score of 0-1 (See Appendix).

8. Adequate bone marrow function (WBC > 3 x 109/L; hemoglobin > 9 g/dl; platelets > 100x 109/L)

9. Adequate liver function (total bilirubin < 1.5 x upper limit of normal, AST < 3 xupper limit of normal, and ALT < 3 x upper limit of normal)

10. Serum creatinine < 1.5 x ULN or calculated creatinine clearance > 50 mL/min (usingthe Cockcroft-Gault formula) Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

11. Women of child-bearing potential (WOCBP) must have a negative serum or urinepregnancy test within 2 weeks prior to study enrollment and must agree to followinstructions for method(s) of contraception for the duration of the study period andat least 3 months after the last dose of chemotherapy is administered. For thepurpose of this study, a woman is considered of childbearing potential followingmenarche and until becoming post-menopausal unless permanently sterile. Permanentsterilisation methods include hysterectomy, bilateral salpingectomy and bilateraloophorectomy. For the purpose of this study, methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effectivebirth control methods and acceptable contraception. Such methods include:

• combined (estrogen and progestogen containing) hormonal contraceptionassociated with inhibition of ovulation:

• oral

• intravaginal

• transdermal

• progestogen-only hormonal contraception associated with inhibition ofovulation:

• oral

• injectable

• implantable

• intrauterine device (IUD)

• intrauterine hormone-releasing system (IUS)

• bilateral tubal ligation

• vasectomized partner

• sexual abstinence

12. WOCBP who are continuously not heterosexually active are exempt from contraceptiverequirements but still must undergo pregnancy testing as described in this section.

13. Males who are sexually active with WOCBP must agree to follow instructions formethods of contraception for the duration of the study period and for at least 3months (duration of sperm turnover) after the last dose of chemotherapy isadministered. In addition, males must be willing to refrain from sperm donationduring this time.

Azoospermic males are exempt from contraceptive requirements.

Exclusion Criteria:

1. Subjects with metastatic or inoperable esophageal or gastroesophageal junctionadenocarcinoma.

2. Subjects with esophageal or gastroesophageal junction squamous cell carcinoma oradenosquamous carcinoma.

3. Prior treatment with chemotherapy or radiation therapy for esophageal orgastroesophageal adenocarcinoma.

4. Prior malignancy active within the previous 3 years that is felt to exclude thepatient from definitive therapy of esophageal or gastroesophageal cancer, or ifprior cancer therapy is felt by the investigator to significantly increase toxicityrisk from the study regimen.

5. Prior history of thoracic or abdominal radiotherapy that would overlap with theplanned treatment volume.

6. Active collagen vascular disease.

7. Subjects with > Grade 1 peripheral neuropathy.

8. Any serious or uncontrolled medical disorder or active infection, that in theopinion of the investigator may increase the risk associated with studyparticipation, study treatment administration or would impair the ability of thesubject to receive study treatment.

9. Known history of hepatitis B or hepatitis C.

10. Clinically unstable cardiac disease including unstable angina, congestive heartfailure, ventricular arrhythmia or known prior QTc > 450msec.

11. History of allergy or hypersensitivity to any of the study drugs or study drugcomponents.

12. Any contraindications to any of the study drugs of the chemotherapy regimens (FLOTor carboplatin/paclitaxel) selected by the investigator. Investigators should referto the local package insert of the chemotherapy drugs.

13. Prisoners or subjects who are involuntarily incarcerated.

14. History of psychiatric illness that precludes completion of informed consentprocess, or which is deemed by the investigators as potentially influencing studycompliance.

15. Known dihydropyrimidine dehydrogenase (DPD) deficiency.

16. Pregnant or breast-feeding women.