Phase I Study of Low-Dose Fractionated Radiotherapy as a Chemosensitizer for Gemcitabine and Erlotinib in Patients With Locally Advanced or Limited 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.