Unresectable cancer of the pancreas was treated with the combination of weekly paclitaxel and external beam irradiation in an effort to improve palliation and extend life expectancy. One hundred twenty-two patients were entered in a multicentered protocol. Thirteen patients were either ineligible, cancelled, or had delinquent data, thus providing 109 for analysis. Unresectable cancer was based on imaging studies (computed tomography or magnetic resonance imaging), all had histologic proof of adenocarcinoma, and none had evidence of metastatic disease or peritoneal seeding. Image-guided radiotherapy treatment consisted of 50.4 Gy in 28 fractions over 5.5 weeks with coplanar anterior/posterior and lateral ports. An initial dose of 45 Gy was given to fields covering the primary tumor plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. A cone down field was used for the last three fractions to encompass the gross tumor volume with a 1- to 1.5-cm margin. Paclitaxel was administered weekly with irradiation in a dosage of 50 mg/m2 as a 3-hour infusion. The median age was 63 and 53% were female. The Karnofsky performance status was greater than or equal to 80 in 81%. Eighty percent were classified T3 or 4; 20% had N1 disease. The primary tumor was located in the pancreatic head in 65%. Eighty-five percent received all six cycles of paclitaxel per protocol, whereas 93% received irradiation with acceptable protocol variation. Field placement, total dose, fractionation, and overall treatment time were given per protocol in greater than or equal to 90%. Acute toxicity (worst per patient) occurred in 39% with grade III (35% of these were asymptomatic neutropenia), 5% with grade IV, and one patient died of infection during the fourth cycle of chemotherapy (grade V). The median follow-up time for alive patients is 20.6 months (range 5-30). The median survival is 11.2 months (95% CI 10.1, 12.3) with estimated 1- and 2-year survivals of 43% and 13%, respectively. External irradiation plus concurrent weekly paclitaxel is well tolerated when given with large-field radiotherapy. The median survival is better than historical results achieved with irradiation and fluoropyrimidines. These data provide the basis for a new Radiation Therapy Oncology Group trial using paclitaxel and irradiation combined with a second radiation sensitizer, gemcitabine, now under way.
The Brown University Oncology Group (BrUOG) developed paclitaxel as a radiation sensitizer to improve local-regional control in pancreatic cancer. 1,2 One rationale for using paclitaxel is the creation of mitotic block by synchronization of cells at G2/M, a relatively radiosensitive phase of the cell cycle. 3,4 Another factor is tumor reoxygenation caused by paclitaxel chemoradiation that contributes to cytotoxicity. 5,6
A phase I study of paclitaxel combined with external irradiation (paclitaxel/RT) for locally advanced pancreatic and gastric cancer found a maximum tolerated dose of 50 mg/m2/wk combined with 6 weeks of irradiation. 2 Dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. In the BrUOG phase II study, 37 patients with locally advanced pancreatic cancer were treated with weekly paclitaxel 50 mg/m2 combined with 50 Gy. 1 Grade III and IV toxicities included two patients with hypersensitivity reactions and one with nonneutropenic biliary sepsis. Of these 37 patients, 2 were inevaluable for response because of hypersensitivity reactions and 1 did not have radiographically assessable disease. Ten of 34 (29%) patients obtained a partial response. Ten initially unresectable patients with stable or improved local disease assessed by computed tomography (CT) scan underwent exploratory laparotomy after paclitaxel/RT. Three underwent complete resection with negative margins. One patient had extensive fibrosis without visible tumor and was not resected. Six had liver metastases detected at surgical exploration that were not apparent on restaging CT scan. Reported here is a large multicentered Radiation Therapy Oncology Group (RTOG) phase II trial with paclitaxel/RT for locally advanced, nonresectable pancreatic cancer.