Chemotherapy, Radiation Therapy, and Cetuximab Followed by Surgery, Docetaxel, and Cetuximab in Treating Patients With Esophageal Cancer or Gastroesophageal Junction Cancer

OBJECTIVES:

Primary

- To determine the pathologic complete response (pCR) rate of neoadjuvant
chemoradiotherapy with OX/5-FU/radiotherapy (RT) plus cetuximab in patients with
resectable adenocarcinoma of the esophagus.

Secondary

- To evaluate the safety of neoadjuvant chemoradiotherapy with OX/5-FU/RT plus cetuximab
in patients with resectable adenocarcinoma of the esophagus.

- To evaluate the safety and tolerability of adjuvant therapy comprising cetuximab and
docetaxel in these patients.

- To carry out exploratory studies to determine if activity of this regimen correlates
with epidermal growth factor receptor (EGFR)-related genetic and pathway activation
markers and circulating endothelial and tumor cells.

OUTLINE: This is a multicenter study.

- Neoadjuvant chemoradiotherapy and cetuximab: Patients receive oxaliplatin intravenously
(IV) over 2 hours on days 1, 15, and 29, cetuximab IV over 1-2 hours on days 1, 8, 15,
22, and 29, and 5-FU IV continuously over 24 hours on days 1-35. Patients also undergo
radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33. Patients then
proceed to surgery.

- Surgery: Patients undergo surgical resection within 4-8 weeks after completion of
neoadjuvant chemoradiotherapy and cetuximab. Patients with an R0 or R1 resection proceed
to adjuvant therapy. Patients whose tumors have not been completely resected or who have
metastatic disease discontinue protocol therapy and receive further therapy at the
discretion of the treating physician.

- Adjuvant therapy: Within 4-8 weeks after surgery, patients receive docetaxel IV over 1
hour on days 1, 8, 15, 22, and 29 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22,
29, and 36. Treatment repeats every 6 weeks for 2 courses in the absence of disease
progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, and then every 6 months for 3-5 years.

Inclusion Criteria:

- Newly diagnosed adenocarcinoma of the esophagus (> 20 cm below the incisors) or
gastroesophageal (GE) junction, untreated with chemotherapy, radiation therapy, and
surgery. Endoscopy with biopsy and dilation was permitted.

- Tumor stage T2N0M0, T3N0M0, T1-3N+M0, or T1-3N0-1M1A as determined by imaging studies
performed no greater than 4 weeks prior to registration, and biopsy, where
appropriate. Celiac nodal metastasis (M1A disease) was permitted if other eligibility
criteria were met. Data from endoscopic ultrasound and endoscopy were required for
staging. The following imaging was required: CT scan with IV contrast and PET or
PET+CT. If the PET/CT incorporates CT with IV contrast, then a separate CT is not
required. If laparoscopy or other relevant procedures were performed, the data were to
be incorporated into stage assignment. Any lesion suspicious for metastasis had to
have been biopsied to prove eligibility.

- Tumor extension into cardia, if present, must have been no more than 2 cm.

- Tumors must have been considered surgically resectable (T1-3, not T4).

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Granulocytes > 1,000/ mm³

- Platelets > 100,000 μL

- Creatinine normal or creatinine clearance > 60 mL/min

- Total serum bilirubin < 1.5 mg/dL

- Fertile patients must use effective contraception

- History of a curatively treated malignancy from which the patient has been
disease-free for ≥ 2 years and has a survival prognosis of > 5 years

Exclusion Criteria:

- Pregnant or breast-feeding.

- Prior severe infusion reaction to a monoclonal antibody

- prior therapy specifically and directly targeting the epidermal growth factor receptor
(EGFR) pathway

- Hypertension

- Uncontrolled diabetes

- Intercurrent illness that would likely interfere with protocol therapy or prevent
surgical resection

- Any of the following within the past 6 months:

- New York Heart Association class III-IV congestive heart failure

- Cerebrovascular accident or transient ischemic attack

- Unstable angina or myocardial infarction