TREATMENT OF LOCALLY ADVANCED DISEASE
CHEMORADIATION

A pilot trial of 5-FU and supervoltage radiation therapy in patients with locally advanced adenocarcinoma of the pancreas served as the foundation for a subsequent study of 5-FU-based chemoradiation by the GITSG. All patients were surgically staged; only patients with disease confined to the pancreas and peripancreatic organs, regional lymph nodes, and regional peritoneum were eligible for treatment. The entire area of malignant disease had to be encompassed within a 400-cm2 area. Radiation therapy was delivered as a split course with 20 Gy given over 2 weeks followed by a 2-week rest. Patients received a total of either 40 or 60 Gy. 5-FU was delivered intravenously at a bolus dose of 500 mg/m2 /d for the first 3 days of each 20-Gy cycle and given weekly (500 mg/m2 ) following the completion of chemoradiation. Patients were randomized to receive 40 Gy plus 5-FU, 60 Gy plus 5-FU, or 60 Gy without chemotherapy. Median survival was 10 months in each of the chemoradiation groups and 6 months for patients who received 60 Gy without 5-FU. These data supported the original double-blind study by Moertel and colleagues that compared 35 to 40 Gy of radiation plus 5-FU to radiation alone. Mean survival was 10.4 months in the chemoradiation group and 6.3 months in the group that received radiation alone. Clinically matched, untreated patients with locally advanced pancreatic cancer (retrospectively reviewed from the Mayo Clinic) were also found to have a median survival of approximately 6 months.

All patients were entered in the GITSG studies following laparotomy, at which time the disease was deemed unresectable by the operating surgeon. Chemoradiation was reasonably well tolerated following major surgery. Approximately 80% of patients completed chemoradiation, and the two fatal septic events were believed not to be treatment related. The most frequent toxic effects were nausea and vomiting, which were seldom severe. The significant morbidity reported with palliative pancreatic surgery suggests that only patients with a high performance status could have recovered rapidly enough to be eligible for these studies. Thus, although surgical staging made for a more uniform study population, it also introduced significant selection bias: only rapidly recovering patients were considered for treatment. Comparison of future studies to these data must account for this selection bias. In subsequent GITSG studies, neither doxorubicin (Adriamycin) used as a radiation potentiator nor multidrug chemotherapy (SMF: streptozocin, mitomycin, and 5-FU) alone or continued after chemoradiation was found superior to 5-FU chemoradiation. Additional chemotherapy beyond 5-FU-based chemoradiation increased toxicity without apparent therapeutic benefit.

EXTERNAL-BEAM RADIATION THERAPY

Treatment planning using high-quality CT allows precise definition of the volume to be treated, enabling the delivery of high-dose EBRT to restricted tumor volumes. The EBRT treatment field encompasses the primary tumor and regional lymph nodes including the celiac axis and the SMA origin. Although these important structures cannot be visualized directly at simulation, their radiographic location is usually at the pedicle of the T12 vertebral body (contrary to the commonly accepted location of the celiac axis at the T12-L1 interspace). In one study, the SMA was found by angiography to arise at the level of the top of L1 in 83% of patients and below the pedicle of L1 in 21%; it arose below the L1-2 interspace in no patients. Because of this anatomic variability, EBRT planning must be individualized by using information from CT, magnetic resonance imaging, or angiographic evaluations. With external irradiation, the isodose lines typically contract in from the superior and inferior field edges, and because of variation in daily treatment set-up, external radiation fields must not encompass T12 or L1 tightly because this risks under-treating the regional lymph nodes.

Treatment simulation is carried out by placing the patient in an arms-up position to avoid an exit dose to the arms. The dose to the primary tumor and regional lymphatics can be specified to the 95% isodose line as a tumor minimum or as an isocentric dose. The limits of normal tissue toxicity guide EBRT to doses of 50.4 Gy (tumor minimum) using fields that rarely exceed 12 × 12 cm. This treatment is usually given in 28 fractions over 5.5 weeks using a four-field technique with anterior-posterior and two lateral fields. Rapid-fractionation irradiation, which delivers 30 Gy (isocenter dose) in 10 fractions over 2 weeks offers the advantages of decreased treatment time, toxicity, and cost. Hyperfractionated irradiation (1.2 Gy twice daily) has also been used for the treatment of unresectable pancreatic cancer, but no improvement in either local tumor control or time to recurrence was found compared with conventional treatment schedules.