An effective locoregional therapy is needed for adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may enhance the effect of radiation therapy (RT). Paclitaxel synchronizes cells at G2/M, a relatively radiosensitive phase of the cell cycle. We have shown that response to paclitaxel and concurrent RT (paclitaxel/RT) was not affected by p53 mutations in non-small cell lung cancer. This finding suggested that paclitaxel/RT was a rational treatment approach for other malignancies that frequently harbor p53 mutations, such as upper gastrointestinal malignancies. We completed a phase I study of paclitaxel/RT for locally advanced pancreatic and gastric cancer. The maximum tolerated dose of paclitaxel was 50 mg/m2/wk for 6 weeks with abdominal RT. The dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. Phase II studies are now under way. Twenty-five patients with locally advanced pancreatic cancer have been entered at the phase II dose level of paclitaxel 50 mg/m2/wk with concurrent RT (total dose, 50 Gy). Thus far, the only grade 3/4 toxicities have been hypersensitivity reactions (n = 2), asymptomatic grade 4 neutropenia (n = 3), and nonneutropenic biliary sepsis (n = 1). Of the first 18 assessable patients with pancreatic cancer treated on the phase II study, six obtained a partial response, for a preliminary response rate of 33%. In the phase II study for locally advanced gastric cancer, 20 patients have been enrolled. Of the first 19 patients who have completed treatment, nine (47%) had grade 3/4 toxicities, including nausea, anorexia, esophagitis, and gastritis. Of the first 16 patients with gastric cancer, complete and partial responses have been observed in one and eight patients, respectively, for a preliminary response rate of 56%. We have also completed treatment on 24 patients with potentially resectable adenocarcinomas of the gastroesophageal junction with neoadjuvant paclitaxel 60 mg/m2 and cisplatin 25 mg/m2, weekly for 4 weeks, with concurrent RT (total dose, 40 Gy) followed by surgical resection. Ten patients (41%) had grade 3/4 toxicities, including neutropenia, nausea, and dehydration. Of 24 patients, four complete responses (17%) and 14 partial responses (58%) were observed, for an overall response rate of 75%. Severe esophagitis was uncommon, making this a well-tolerated outpatient regimen for adenocarcinomas of the distal esophagus. These findings demonstrate that paclitaxel-based chemoradiation for locally advanced upper gastrointestinal malignancies is well-tolerated with substantial activity.
