Eligibility included cytologic or histologic evidence of locally unresectable adenocarcinoma of the pancreas, not amenable for complete surgical resection based on clinical or radiographic evaluation (laparoscopy was not required). Patients with small-cell carcinoma, mucinous cystadenocarcinoma, or islet cell or papillary cystic neoplasm were not eligible. Patients must also have been at least 18 years of age, had an ECOG performance score of 0 to 2, and received no prior chemotherapy or radiotherapy. Eligible patients had an absolute granulocyte count of 2.0 × 109/μL or greater, platelet count greater than 100,000/μL, total bilirubin of less than 3 mg/dL (unless secondary to biliary obstruction or cholangitis), AST less than 5× upper limit of normal, albumin greater than 2.5 g/dL, and serum creatinine 1.5× or less than upper limit of normal. Patients were not eligible if they had a history of active collagen vascular disease or signs of recent peptic or duodenal ulcer (eg, < 3 months). Other contradictions included serious concomitant systemic disorders or active infections. Women of childbearing potential had to have had a negative pregnancy test within 2 weeks of study entry and were strongly encouraged to use effective methods of contraception. All patients provided written informed consent before initiation of therapy. This was an intergroup study lead by the ECOG through the National Cancer Institute. No industry support was involved in the conduct of the study or analysis.
After registration, patients were stratified by performance status (0 v 1) and prior weight loss within previous 6 months (< 10% v ≥ 10%) and randomly assigned to receive gemcitabine alone (arm A) or gemcitabine plus radiotherapy (arm B). Patients in arm A received gemcitabine 1,000 mg/m2 intravenously (over approximately 30 minutes) per week for 6 weeks, followed by a 1-week rest. After the week of rest, treatment was resumed at 1,000 mg/m2 weekly for 3 weeks, followed by 1 week rest, for five additional 4-week cycles. All dosages of gemcitabine were based on calculated body-surface area, using actual height and weight.
Patients in arm B received gemcitabine 600 mg/m2 intravenously (over 30 to 60 minutes) beginning on the first day of radiation therapy (before radiation), then weekly thereafter during radiation. The radiation dose was 1.8 Gy per daily fraction, 5 days per week, for a total dose of 50.4 Gy administered in 28 fractions over 5.5 weeks, with a required field reduction after 39.6 Gy. Three-dimensional (3D) treatment planning (with conformal radiotherapy capabilities) was highly encouraged. A 3D benchmark was to be completed and submitted to the Quality Assurance Review Center, which conducted two separate reviews: a rapid review (at initiation of radiation) and final review (at completion of radiation). Intensity modulated radiation therapy was not permitted in this study. Patients underwent computed tomography (CT) simulation. The initial large fields, designed to encompass the planning target volume, received 39.6 Gy in 22 fractions. This included the gross target volume (GTV; defined by CT scan and/or surgically placed clips) plus a 3-cm margin but had to be less than 400 cm2 in anterior-posterior to posterior-anterior projection. In addition, the local/regional lymph nodes adjacent to the GTV were included, with at least a 1.5-cm margin, primarily the peripancreatic and pancreatoduodenal defined by the duodenal loop, celiac nodes, porta hepatis, and nodes around the superior mesenteric vessels. Smaller margins were allowed to accommodate normal tissue dose requirements, providing target coverage was adequate.
As part of the 3D treatment planning, surrounding normal tissues including liver, each kidney separately, and spinal cord were reconstructed, and dose-volume histograms for those critical structures were submitted for review. The small or boost fields encompassing the planning target volume included the GTV with a 2-cm margin and received an additional 10.8 Gy delivered in six fractions at 1.8 Gy per fraction. Approximately 4 weeks after completion of radiation, gemcitabine was resumed at full dosage (arm A) for a total of five cycles.
History was taken and physical examination performed before initiation of therapy, at week 6, and then at day 1 of each cycle of gemcitabine. Patients were deemed unresectable after surgical consultation based on presence of superior mesenteric vein or portal vein occlusion, superior mesenteric artery or hepatic artery encasement, gross regional lymphadenopathy, or metastatic disease. Abdominal CT scan for tumor evaluation was performed before study entry, at week 8, and within 4 weeks of chemotherapy completion. Other scans were to be performed as warranted by symptoms of clinical progression or to document response (> 4 weeks after first response noted). During therapy, hematologic parameters and chemistries were collected weekly along with height, weight, and performance status. Chemistries were repeated monthly during therapy. Patient-reported health-related QOL (HRQOL) was assessed using the Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) questionnaire, which includes 27 items to assess physical, functional, emotional, and social well-being and 18 items to assess hepatobiliary-specific concerns.18
The FACT-Hep was administered at baseline, week 6, week 15 or 16, and 9 months after baseline, even if therapy had been discontinued.
For all patients experiencing grade 3 or 4 toxicities (except grade 3 nausea/vomiting), one dose level was decreased, as listed in . If patients experienced grade 3 or 4 febrile neutropenia (≥ 38.3°C), gemcitabine was delayed until ANC was 1,000 μL or greater, and when restarted, gemcitabine was reduced by one level (). If either ANC was less than 1,000/mm2 or platelets were less than 50,000, gemcitabine was delayed until resolution and reinstituted at one dose level reduction. Dose reductions based on nonhematologic toxicities (such as nausea and/or vomiting) applied to the remainder of treatment. If gemcitabine was delayed because of grade 4 nonhematologic toxicity, it could be resumed at one dose level reduction once the toxicity improved to less than grade 2. Doses held back because of toxicity would not be administered at a later time. If toxicity did not resolve to less than grade 2 within 2 weeks or if more than two dose reductions of gemcitabine were required, the patient's protocol treatment was to be discontinued.
The primary end point of this trial was OS in patients treated with gemcitabine alone versus gemcitabine plus radiation therapy. Secondary objectives included objective response rate as per RECIST (Response Evaluation Criteria in Solid Tumors), PFS, toxicity, and HRQOL.
The proposed sample size of 316 eligible patients was planned to provide at least 88% power to detect a 50% difference in median survival while maintaining a significance level of 2.5% in a one-sided log-rank test, assuming exponential failure and median survival of 8 months with gemcitabine alone and 12 months with gemcitabine and radiation. The one-sided test was prespecified in the design phase of the study to evaluate the main objective to test whether combined-modality therapy improved survival. Interim evaluations of the study were planned at 25%, 50%, and 75% of mortalities as well as the final analysis. Group sequential methods based on an O'Brien-Fleming and DeMets approach were also employed to adjust the boundaries if the actual interim analyses did not correspond with the projected information times provided in the design.12,13
This study was monitored for early stopping in favor of the null hypothesis using repeated CI methodology similar to that described by Jennison et al.19
At each interim analysis, the nominal (1 to 2 × alpha) CI on the OS hazard ratio comparing the gemcitabine alone arm with the gemcitabine plus radiation therapy arm was computed, where alpha was the nominal one-sided significance level of the use-function boundary at the information fraction for the particular analysis time. If the CI did not contain the target alternative of 1.50, then the data monitoring committee would consider closing an arm of the trial or stopping the study early for overall lack of treatment differences.
HRQOL was assessed using the 45-item FACT-Hep, administered at baseline, week 6, week 15 or 16, and 9 months postbaseline. FACT-Hep total scores were calculated to obtain a total measure of HRQOL including hepatobiliary symptoms. The FACT-Hep subscale score was calculated to indicate disease-specific concerns. Subscales from the FACT were calculated to assess physical and functional well-being. The trial outcome index was calculated by summing the FACT physical well-being, functional well-being, and hepatobiliary subscale scores to provide a more focused assessment of HRQOL, disease symptoms, and functional status. FACT-Hep scoring was performed according to manual instructions (http://www.facit.org
Standard descriptive and graphical analyses were used initially to explore unusual observations, missing data patterns, and the relationship between variables. At each time point, QOL of two treatment groups and QOL change from baseline were compared using the Wilcoxon two-sample tests with a two-sided significance level of .05. Nine individual items from the FACT-Hep were selected to examine the proportion of participants with clinically significant symptoms.