Oxaliplatin and Irinotecan in Recurrent or Metastatic Esophageal and Gastroesophageal (GE) Junction Carcinoma

Esophageal cancer represents the seventh cause of cancer death in American men, and more than
90% of patients diagnosed with esophageal cancer will ultimately die of their disease. In the
United States, 13,900 new cases of esophageal cancer and 13,000 deaths from esophageal cancer
are anticipated in 2003 (Jemal et al, 2003). The lifetime risk of esophageal cancer is 0.8%
for men and 0.3% for women (Ries et al, 2002). The risk increases with age, with a mean age
at diagnosis of 67 years (Ries et al, 2002; Daly et al, 2000). Adenocarcinoma of the
esophagus or gastroesophageal junction, a previously rare disease, is rapidly increasing in
incidence in the United States and western countries and now accounts for more than half of
newly diagnosed disease (Devesa et al, 1998).

Half of patients diagnosed with esophageal cancer present with overt metastatic disease, and
chemotherapy is the mainstay of palliation in this setting. In patients who present initially
with locoregional disease, the majority will eventually develop metastatic disease as well,
with or without local recurrence of disease. Metastatic esophageal carcinoma is an incurable
disease with median survival duration of 4 to 8 months. Combination chemotherapy, most often
cisplatin-based, results in partial responses in 25% to 50% of patients with metastatic
disease and rare complete responses, including a 35% response rate reported for the commonly
used combination of cisplatin and fluorouracil (Ilson et al, 1996). Recent chemotherapy
trials indicate an overlap in response rates for metastatic adenocarcinoma and squamous
carcinoma carcinoma of the esophagus (Ilson et al, 1997). Responses to chemotherapy are
generally short-lived, and toxicity of cisplatin-based chemotherapy, particularly in the
palliation of metastatic disease, is often substantial and underscores the need to identify
new agents in the treatment of esophageal carcinoma.

Inclusion Criteria:

- All patients must have histologically or cytologically confirmed diagnosis of squamous
cell carcinoma or adenocarcinoma of the esophagus. Patients with tumors of the
gastroesophageal junction were eligible if at least 50% of the tumor involved the
esophagus.

- Patients must have locally advanced (i.e. unresectable) or metastatic disease

- All sites of disease must be assessed and designated as measurable or non-measurable
disease as documented by CT, MRI, X-ray physical Each of the criteria in the following
section must be met in order for a patient to be eligible for registration.

- Patients may have received prior radiotherapy if there has been complete recovery from
all radiation-induced toxicities. At least 4 weeks must have been elapsed from the
completion of radiation therapy to the time of registration. If lesions within the
radiation port are to be used to assess response to therapy, those lesions must have
demonstrated clear progression by the criteria outlined in Section 10.2d following
completion of radiation therapy.

- Patients must have adequate bone marrow reserve as documented by absolute neutrophil
count (ANC) > 1,500 microliters and platelets > 100,000/microliter obtained within 14
days prior to registration.

- Patients must have adequate hepatic as documented by serum bilirubin < 1.5 x the
institutional upper limit of normal. Serum transaminase (SGOT or SGPT) must be < 1.5 x
the institutional upper limit of normal serum unless the liver is involved with tumor,
in which case serum transaminase (SGOT or SGPT) must be < 5 x the institutional limit
of normal. These tests must be obtained within 14 days prior to registration.

Patients must have a creatinine < 1.5 x the institutional upper limit of normal or a
creatinine clearance of > 30 cc/min calculated using the following formula obtained within
28 days prior to registration.

Calculated Creatinine Clearance = (140-age) X wt (kg) X (0.85 if female) 72 X creatinine
(mg/dl)

These tests must have been performed within 28 days prior to registration.

- All patients must be 18 years of age or older

- Patients must have a Zubrod performance of 0-2

Exclusion Criteria:

- Patients must not have received prior chemotherapy for chemotherapy for advanced or
metastatic esophageal cancer. Chemotherapy given adjuvantly or as a radiosensitizer is
allowed if more than 8 weeks have elapsed since the treatment was completed and they
have recovered from any treatment related toxicity.

- Patients must not have a surgical procedure for esophageal cancer within 4 weeks prior
to registration. Patients must have completely recovered from all surgery prior to
registration.

- Patients with any evidence of active or uncontrolled infection, recent myocardial
infection, unstable angina, or life-threatening arrhythmia are not eligible.

- Patients with severe psychiatric disorder are not eligible.

- Patients with known brain metastasis are not eligible. However, brain-imaging studies
are not required for eligibility if the patient has no neurological signs or symptoms.
If brain-imaging studies are performed, they must be negative for disease.

- No other prior malignancy is allowed except for adequately treated basal cell or
squamous cell carcinoma, in situ cervical cancer, or adequately treated Stage I and II
cancer from which the patient is in complete remission, or any other malignancy from
which the patient has been disease-free for 5 years.

- Patients should not have active infection.

- Patients should not have psychological, familial, sociological, or geographical
conditions that do not permit medical follow-up and compliance with study protocol.

- Except for cancer-related abnormalities, patients should not have unstable or
pre-existing major medical conditions.

- Patients should not have any immediate life-threatening complications of their
malignancies.