PET Scan Imaging in Assessing Response in Patients With Esophageal Cancer Receiving Combination Chemotherapy

• PET/CT response between treatment arms [ Designated as safety issue: No ]
• pCR rate among induction treatment PET/CT scan responders [ Designated as safety issue: No ]
• PFS and OS at 8 months [ Designated as safety issue: No ]

RATIONALE: PET scans done during chemotherapy may help doctors assess a patient's response to treatment and help plan the best treatment.

PURPOSE: This randomized phase II trial is studying PET scan imaging in assessing response in patients with esophageal cancer receiving combination chemotherapy.

OBJECTIVES:

Primary

• To induce a complete pathologic response (pCR) rate of 20% in positron emission tomography (PET) scan non-responders treated with either induction FOLFOX or carboplatin/paclitaxel, who then crossover to the other regimen during radiotherapy.

Secondary

• To compare PET/CT response between induction treatment arms.
• To compare pCR between induction treatment arms among PET/CT scan responders.
• To directly compare pCR between induction treatment arms among non-responders if both treatment regimens are found to be efficacious.
• To determine 8-month progression-free survival (PFS) in PET/CT scan responders, and in non-responders treated with alternative crossover chemoradiotherapy.
• Estimate the PFS and overall survival (OS) curves, overall and among PET responders and PET/CT non-responders by induction treatment.
• To determine the rate of postoperative anastomotic leak after neoadjuvant chemotherapy followed by chemoradiation.
• To evaluate immunohistochemistry and RT-PCR of ERCC1, and genetic polymorphisms of ERCC1, XPD, and XRCC1.
• To evaluate status and levels of methylation of nine candidate biomarker genes as well as expression levels of selected specific microRNAs, which will be correlated with chemoradiation response.
• To compare the quality of life (QOL) of responders and nonresponders (as determined by PET/CT scanning) to presurgical treatment for esophageal cancer, in terms of global QOL, physical symptoms, physical functioning, and emotional well-being.
• To examine the association between OS and QOL in esophageal cancer patients treated with chemotherapy, chemoradiation therapy, and surgery.

OUTLINE: This is a multicenter study. Patients are stratified according to T-stage (T1-2 vs T3-4) and nodal status (N0 vs N+). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive modified FOLFOX-6 therapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-5. Treatment repeats every 14 days for 3 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreased by ≥ 35%) receive 3 additional courses of FOLFOX-6 therapy and undergo concurrent radiotherapy (RT) (3D-conformal or intensity-modulated) once daily, 5 days a week, for approximately 6 weeks. Patients without responsive disease (tumor metabolic activity did not decrease by 35%) cross over to arm II during RT.
• Arm II: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 2 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreases ≥ 35%) continue to receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour once weekly for 5 weeks and undergo RT (3D-conformal or intensity-modulated) once a day, 5 days a week, for approximately 6 weeks. Patients without responsive disease (metabolic activity did not decrease by 35%) cross over to arm I during RT.

Within 4-10 weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgery at the discretion of the treating team.

Patients may undergo blood sample collection at baseline and periodically during study for correlative studies. Patients may also complete quality-of-life questionnaires at baseline and periodically during study.

After completion of study therapy, patients are followed up periodically for 5 years.

• Adenocarcinoma of the Gastroesophageal Junction
• Esophageal Cancer

• Drug: FOLFOX regimen
  Given IV
• Drug: carboplatin
  Given IV
• Drug: fluorouracil
  Given IV
• Drug: leucovorin calcium
  Given IV
• Drug: oxaliplatin
  Given IV
• Drug: paclitaxel
  Given IV

• Experimental: Arm I
  Patients receive modified FOLFOX-6 therapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-5. Treatment repeats every 14 days for 3 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreased by ≥ 35%) receive 3 additional courses of FOLFOX-6 therapy and undergo concurrent radiotherapy (RT) (3D-conformal or intensity-modulated) once daily, 5 days a week, for approximately 6 weeks. Patients without responsive disease (tumor metabolic activity did not decrease by 35%) cross over to arm II during RT.
  Interventions:

  • Drug: FOLFOX regimen
  • Drug: fluorouracil
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
• Experimental: Arm II
  Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 2 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreases ≥ 35%) continue to receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour once weekly for 5 weeks and undergo RT (3D-conformal or intensity-modulated) once a day, 5 days a week, for approximately 6 weeks. Patients without responsive disease (metabolic activity did not decrease by 35%) cross over to arm I during RT.
  Interventions:

  • Drug: carboplatin
  • Drug: paclitaxel

DISEASE CHARACTERISTICS:

• Surgically resectable, histologically confirmed esophageal adenocarcinoma, including Siewert gastroesophageal (GE) junction adenocarcinomas Types 1 and 2

• T1 N1-3 M0 or T2-4 N any M0 as determined by endoscopic ultrasound (EUS) and PET/CT (histologic confirmation of lymph involvement is not required)

  • All patients must have locoregional staging determined by EUS if technically feasible
  • All disease (tumor and nodes) must be both surgically resectable and capable of containment in a radiotherapy field
  • Endoscopy reports should clearly state both the T and N stage
  • No T4 tumor with clear evidence of invasion of the vertebral column, heart, great vessels, or tracheobronchial tree
• No evidence of distant metastases (as determined by EUS or PET/CT)
• Patients with cervical, supraclavicular, or other nodal disease that is either not included in the radiation field or is not able to be resected at the time of esophagectomy are not eligible
• Patient must have pre-resection tissue available for central pathology review
• Patients must have detectable fluorine-18-labeled deoxyglucose (FDG) uptake on baseline PET/CT scan of primary tumor

PATIENT CHARACTERISTICS:

• ECOG performance status 0-1
• ANC ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Creatinine clearance ≥ 60 mL/min
• AST/ALT ≤ 2.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test

• No prior malignancy within 5 years, with the exception of basal or squamous cell skin cancers, or in situ bladder or cervical cancer

  • Patients with prior malignancy treated with surgery only and disease-free for more than 5 years are eligible
• No history of severe hypersensitivity reaction to Cremaphor® EL
• No known contraindication to the use of fluorouracil, taxanes, or platinum compounds

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior thoracic radiotherapy (RT), abdominal RT, or chemotherapy
• No concurrent epoetin