Between January 18, 2005 and February 7, 2006, 94 patients were enrolled from 36 institutions. Eleven patients were ineligible on the basis of inability to meet eligibility criteria (most were inadequate lab studies), and one patient withdrew consent. Therefore, 82 patients were eligible for inclusion in the analysis. Pretreatment characteristics for eligible patients are listed in .
Efficacy End Points
The estimated 1-year survival rate was 47% (95% CI, 36% to 57%; ) and was not statistically higher than in RTOG 9812 (one-sided log-rank test P = .49 for this study v RTOG 9812). The median survival time for patients in this study was 11.9 months (95% CI, 9.9 to 14.0 months). At the time of analysis, two patients were alive with less than 1 year of follow-up. The estimated 1-year PFS rate was 30% (95% CI, 20% to 40%). The median PFS time was 8.6 months (95% CI, 6.9 to 10.5 months). The best local responses was stable disease (50 of 82; 61%), followed by partial response (21 of 82; 26%).
The estimated 1-year survival rate was 47% (95% CI, 36% to 57%).
The 12-month, actuarial, radiographic, local and regional progression rates were 29.7% (95% CI, 19.6% to 40.0%) and 8.6% (95% CI, 2.5% to 14.8%), respectively.
Events Possibly Related to Bevacizumab
Bleeding occurred in five patients (6.1%) at 83, 127, 179, 180, and 316 days after the start of chemoradiotherapy. None of these events occurred during chemoradiotherapy; two occurred during maintenance chemotherapy. None of these events were related to the acute effects of chemoradiotherapy at the tumor site. Gastrointestinal perforation occurred in three patients (3.7%) at 195 (grade 5), 231 (grade 4), and 286 (grade 3) days after the start of chemoradiotherapy. The grade 4 event resulted in discontinuation of protocol therapy, and the other two occurred after protocol therapy had been discontinued. No arterial thrombotic events were reported, but deep venous thrombosis was reported in three patients; one was grade 3, and two were grade 4. Two instances of grade 3 hypertension were reported. One patient died 23 days after the first dose of bevacizumab from an abdominal bleed that was confirmed at autopsy to be related to an endoscopic retrograde cholangiopancreatography injury.
Sixty-six (80%) of 82 patients experienced grade 3 or greater toxicity reported as definitely, probably, or possibly related to treatment. The worst nonhematologic toxicity was grade 3 or greater in 54 (65.9%) of 82 patients. The most common events were gastrointestinal toxicity in 29 (35.4%) of 82 patients and constitutional symptoms in 22 (26.8%) of 82 patients (). During chemoradiotherapy, 18 (22.0%) of 82 patients experienced grade 3 or greater gastrointestinal toxicity () compared with 14 (17.3%) of 81 during maintenance chemotherapy (). There were three deaths reported as definitely, probably, or possibly related to treatment. One patient experienced sudden death 175 days after the initiation of treatment; one patient experienced infection of the peritoneal cavity and died 110 days after beginning treatment; and one patient experienced colonic perforation and died 195 days after the initiation of treatment. There were an additional two deaths reported as unlikely to be related to treatment or as unrelated to treatment 23 and 155 days after treatment initiation.
Select Adverse Events Reported As Definitely, Probably, or Possibly Related to Treatment and Occurring at Any Time (N = 82)
Select Adverse Events Reported As Definitely, Probably, or Possibly Related to Treatment and Occurring During Chemoradiation (N = 82)
Select Adverse Events Reported As Definitely, Probably, or Possibly Related to Therapy Occurring During Maintenance Chemotherapy (N = 81)
When the first 25 and the first 50 assessable patients were evaluated for toxicity, neither the early stopping criterion for USAEs nor that for UAEs was met. Additionally, only four of the first 74 assessable patients experienced UAEs; however, at the final analysis, 9 patients of the first 74 assessable patients had USAEs. Therefore, on the basis of these data, the rate of USAEs as defined in this protocol is greater than 15% but not greater than 35%.
Chemotherapy Dose Adjustments for Toxicity
During chemoradiotherapy, capecitabine was adjusted for toxicity in 29% of patients, and bevacizumab was held or discontinued in 16% of patients. A median of three cycles of maintenance chemotherapy was given (range, 0 to 10.3 cycles). The gemcitabine dose was modified, held, or discontinued in 89% of patients, and the bevacizumab dose was held or discontinued in 50% of patients during the maintenance phase.
Radiotherapy Quality Assurance
All the radiation treatment plans were reviewed after the completion of protocol therapy, and deviations in either tumor contouring or treatment field design were noted. Major (unacceptable) deviation was defined as contoured gross tumor volume 5 cm greater than the actual tumor size on the basis of diagnostic imaging in any dimension, inability to contour gross tumor, or the use of block margin greater than 5 cm. There were 11 (13.4%) unacceptable deviations. All were related to excessive inclusion of normal tissue in the contoured volume. There was a significant correlation between major deviation and the incidence of grade 3 or greater gastrointestinal toxicity both during chemoradiotherapy (45% v 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; P = .05) and during maintenance chemotherapy (45% v 13%; adjusted odds ratio, 5.7; 95% CI, 1.45 to 22.8; P = .01).
Ten patients underwent surgical exploration and attempted resection at a median of 7.1 weeks after the last dose of bevacizumab (range, 4.1 to 14.7 weeks). Seven of these underwent pancreaticoduodenectomy, and one underwent distal pancreatectomy. Five of the eight patients who underwent resection had margin-negative (R0) resection, and three had resection with indeterminate margins. Two were determined to be unresectable. There was one perioperative complications reported: a grade 3 perioperative infection.