The activity of paclitaxel in gastrointestinal tumors

Gastrointestinal malignancies, which are common around the world, are relatively refractory to available cancer chemotherapeutic agents, necessitating a search for new agents able to improve palliation and survival of patients with advanced disease. Currently, metastatic or local-regional unresectable carcinoma of the esophagus or gastroesophageal junction carries a dismal prognosis. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a new mitotic spindle inhibitor, has been studied in patients with advanced gastrointestinal carcinoma. In this phase II National Cancer Institute-sponsored study, previously untreated patients with unresectable local-regional or metastatic carcinoma of the esophagus or gastroesophageal junction (either squamous cell carcinoma or adenocarcinoma) received a starting dose of paclitaxel of 250 mg/m² administered by a 24-hour intravenous infusion (with premedication) repeated every 21 days; all patients received subcutaneous granulocyte colony-stimulating factor 5 μg/kg daily 24 hours after the completion of the paclitaxel infusion. Fifty-one of 53 patients were assessable for response and response duration. Thirty-three patients had adenocarcinoma and 18 had squamous cell carcinoma. Sixteen (31%) patients achieved a response (one complete and 15 partial) and 11 (22%) achieved a minor response. Among 33 patients with adenocarcinoma, 12 (36%; 95% confidence interval, 14% to 58%) achieved either a complete (one patient) or partial (11 patients) response and six patients (18%) had a minor response. Four (22%; 95% confidence interval, 3% to 41%) of 18 patients with squamous cell carcinoma had a partial response and four (22%) had a minor response. At a median follow-up of 12+ months, 28 patients remain alive with an actuarial median survival duration of 10.2 months (range, 2 to 20+ months). These data suggest that paclitaxel is active against adenocarcinoma as well as squamous cell carcinoma of the esophagus. In a subsequent study, the combination of paclitaxel (175 mg/m² over 3 hours on day 1), cisplatin (20 mg/m² on days 1 to 5), and 5-fluorouracil (1,000 mg/m²/d in the first 10 patients but then reduced to 750 mg/m²/d, given as a continuous infusion on days 1 to 5) repeated every 28 days was given to patients with advanced adenocarcinoma or squamous cell carcinoma of the esophagus. Of 46 patients accrued (target accrual, 60), 35 are men and 11 are women, 30 have adenocarcinoma and 16 have squamous cell carcinoma. Among 39 patients evaluated for response so far, one has had a complete response and 16 have had partial responses (overall response rate, 44%; 95% confidence interval, 28% to 59%). Five patients have had a minor response. The median granulocyte nadir was 1,200/μL. Seven patients have been hospitalized to manage fever associated with neutropenia. With the reduced starting dose of 5- fluorouracil, tolerance has improved substantially both in the inpatient and outpatient settings, resulting in a low frequency of grade 3 or 4 nonhematologic toxicity. Preliminary data suggest that this is an active combination against squamous cell carcinoma and adenocarcinoma of the esophagus. A phase III study may be warranted to define the contribution of paclitaxel. Thus far, paclitaxel has demonstrated limited or no activity in trials conducted in patients with pancreatic, colorectal, or gastric carcinoma. Clinical investigation continues to further explore the activity of paclitaxel in gastrointestinal malignancies.