Study of Low-Dose Fractionated Radiotherapy in Patients With Locally Advanced Metastatic Pancreatic Cancer

Pancreatic cancer is nearly universally fatal, with approximately 38,000 new cases and
34,000 deaths expected in 2008.1 The majority of patients present with disease that is not
amenable to curative resection. For patients with metastatic disease, one standard treatment
is the combination of gemcitabine with the small molecule epidermal growth factor tyrosine
kinase inhibitor erlotinib. This combination results in a modest survival benefit compared
to single agent gemcitabine.2

For patients presenting with localized but unresectable disease, the standard treatment
remains controversial. Early studies demonstrated that chemotherapy and radiation was
superior to either modality alone.3 However, recent studies of systemic therapy alone have
typically included a small but real minority of patients with locally advanced disease,
supporting that systemic therapy alone is a reasonable treatment option.2 Adding to the
confusion are recent European reports that systemic therapy alone may be superior to
combined modality therapy, at least when used initially.4 The greatest benefit of external
beam radiotherapy may be after a period of full-dose chemotherapy alone, to ensure that
rapid metastases do not develop.5 A limitation of beginning treatment with conventional
external beam radiotherapy is a requirement to reduce dosing of gemcitabine by 40-50%. Given
the safety and preclinical rationale for LDRT, we propose this phase I study to evaluate the
safety of LDRT with standard dosing of gemcitabine and erlotinib in patients with locally
advanced or limited metastatic pancreatic cancer. Patients will be enrolled in cohorts with
escalating doses of low dose radiotherapy. Radiation ports will be uniform between patients
as described in Section 5.6 below. As LDRT is administered to sites of disease in liver and
abdominal cavity to iliac crest, patients with metastatic disease confined to these areas
will be eligible. For patients with locally advanced disease, this protocol also has high
rationale, as the overwhelming majority of patients develop and succumb to recurrences in
liver and abdominal cavity,10 areas which would be covered by the proposed radiation field.
The dose of 2880 cGy is the limit because of kidney and other upper abdominal organ
potential for toxicity.

Inclusion Criteria:

- Patients must have a diagnosis of adenocarcinoma of the pancreas that is not amenable
to curative surgical resection. Patients with locally advanced unresectable disease
and those patients with metastatic disease that can be encompassed in the radiation
fields for this study (as assessed by treating radiation oncologist) are eligible.

- Patients may not have received any prior chemotherapy for locally advanced or
metastatic pancreatic cancer. Prior adjuvant chemotherapy completed >1 year
previously is allowed.

- Patients must be able to provide informed consent and HIPAA consent.

- Patients must be ≥18 years of age

- Adequate hematologic and organ function:

- ANC ≥ 1,000/μL, platelets ≥ 100,000/μL, hemoglobin ≥ 9.0/dL

- Bilirubin: ≤1.5X ULN

- ALT/AST < 3.0 X upper limit of normal

- Serum Creatinine: WNL

- Albumin > 2.5 g/dL

- Measurable and non-measurable disease are permitted

- ECOG performance status 0-1

- Patients must be able to swallow oral medications

- Patients must be able to comply with study and follow up procedures

Exclusion Criteria:

- No prior radiation therapy to the abdomen.

- Patients must not have any other active illness (e.g. active/uncontrolled infection,
uncontrolled cardiac disease, etc.) that would preclude safe therapy in the judgment
of the treating physicians. Patients may be enrolled while still on antibiotics as
long as clinical signs of active infection are absent.

- Patients with concurrent active malignancy requiring therapy are not eligible.
Patients with a history of malignancy within any timeframe not requiring ongoing
therapy are eligible.