Tara M. Breslin, Nora A. Janjan, Jeffrey E. Lee, Peter W. T. Pisters, Robert A. Wolff, James L. Abbruzzese, Douglas B. Evans

Pancreatic Tumor Study Group: Departments of Surgical Oncology (TMB, JEL, PWTP, DBE), Radiation Oncology (NAJ), and Gastrointestinal Oncology and Digestive Diseases (RAW, JLA), The University of Texas M. D. Anderson Cancer Center, Houston, TX

Received 6/4/98 Accepted 5/5/98

7. NEWER RADIATION SENSITIZING AGENTS

Paclitaxel is a plant product isolated from the stem bark of Taxus brevifolia, the western yew, a small evergreen indigenous to the Pacific Northwest (31). Paclitaxel enhances the polymerization of tubulin to stable microtubules, inhibiting spindle cell function during mitosis, thereby preventing normal cell replication. Cells exposed to paclitaxel experience growth arrest in the G2/M phase of the cell cycle – a state during which they are especially sensitive to irradiation. In clinical trials, patients with a variety of solid tumors including ovary, breast, and metastatic pancreatic adenocarcinoma have demonstrated objective responses to taxanes (paclitaxel and docetaxel) despite significant tumor burdens which failed to respond to conventional therapy (31, 32). Recently, Safran and colleagues from the Brown University Oncology Group performed a phase I study using paclitaxel and concurrent EBRT in patients with locally advanced pancreatic and gastric adenocarcinoma (33). Dose limiting toxicity was due to abdominal pain, nausea, and anorexia and occurred at 60 mg/m2/week. Four objective (radiographic) partial responses were observed in 13 patients with pancreatic cancer.

The above data provide the rationale for the recently reported study from Vanderbilt of preoperative paclitaxel (30 to 75 mg/m2/wk.) and concurrent standard-fractionation EBRT (45 Gy; 1.8 Gy/fraction) for patients with potentially resectable adenocarcinoma of the pancreatic head (34). Five patients have been entered and four have undergone successful pancreaticoduodenectomy and are alive with a minimum follow-up of 15 months. At MDACC, paclitaxel (60 mg/m2/wk for 3 wks) has been combined with rapid-fractionation chemoradiation (30Gy/2 wks; 3 Gy/fraction). Preliminary experience with this regimen has demonstrated minimal toxicity and improved histologic response in the resected pancreatic tumor compared to previous studies with 5-FU–based preoperative chemoradiation (Evans, unpublished data).

Gemcitabine (2',2'-difluorodeoxycytidine, Gemzar ) is a deoxycytidine analogue capable of inhibiting DNA replication and repair. Following a phase I study (35), gemcitabine was evaluated in a multicenter trial of 44 patients with advanced pancreatic cancer (36). While only five objective responses were documented, the investigators noted frequent subjective symptomatic benefit, often in the absence of an objective tumor response. Toxicity appeared minor and included myelosuppression, particularly thrombocytopenia, as well as a flu-like syndrome and mild hemolytic-uremic syndrome. Based on these observations, two subsequent trials of gemcitabine in patients with advanced pancreatic cancer have been completed. In one randomized trial, gemcitabine was compared to 5-FU in previously untreated patients (37). Patients treated with gemcitabine had a median survival of 5.65 months compared to 4.41 months (p=0.0025) in those treated with 5-FU. Twenty-four percent of patients treated with gemcitabine were alive at 9 months compared to 6% of patients treated with 5-FU. In addition, more clinically meaningful effects on disease-related symptoms (pain control, performance status, weight gain) were seen with gemcitabine (23.8% of patients) than with 5-FU (4.8% of patients). Similar systemic effects and demonstrable disease responses were documented in patients who were treated with gemcitabine after experiencing disease progression while receiving 5-FU (38).

Gemcitabine is also a potent radiation sensitizer of human pancreatic cancer cells in vitro, supporting studies examining its use in vivo. Laboratory studies suggest that the inhibitory effect of gemcitabine on DNA synthesis (when combined with irradiation) is prolonged in tumor compared to normal tissues (39). This may provide a window of opportunity for the combination of gemcitabine and EBRT when delivered in a fractionated schedule. Such data provide the basis for the recently reported phase I studies of this drug-radiation combination. Blackstock and colleagues treated 8 patients with combined standard-fractionation EBRT (50.4 Gy/5.5 wks; 1.8 Gy/fraction) and twice weekly, escalating doses of gemcitabine (20 mg/m2, 40 mg/m2, 60 mg/m2); no grade IV toxicites were observed, the MTD has not been reached (40).> McGinn and colleagues reported the treatment of 13 patients in a multi-institutional setting with standard-fractionation EBRT (50.4 Gy) and an escalating weekly dose of gemcitabine (200 mg/m2, 300 mg/m2, 400 mg/m2) (41). Three patients required hospital admission for nausea and vomiting. Enrollment continues at a gemcitabine dose of 500 mg/m2/wk, and the MTD has not yet been reached. Wolff and colleagues from MDACC have reported a phase I study of rapid-fractionation EBRT (30 Gy/2 wks; 3 Gy/fraction) and concomitant weekly gemcitabine in patients with locally advanced adenocarcinoma of the pancreatic head (42).> Gemcitabine was given during the first two weeks of irradiation and continued weekly to complete a 7-week course of systemic therapy. At this schedule of administration, 500 mg/m2/wk was judged to be above the MTD for this drug-radiation combination. Five of 10 evaluable patients demonstrated response to treatment with an occasional impressive radiographic response (figure 6).

Figure 6. Computed tomography scans before (left) and after (right) treatment with concurrent gemcitabine and external-beam radiation therapy. The arrow identifies the site of the primary adenocarcinoma within the pancreatic head.

Hoffman and colleagues have reported a phase I study of preoperative standard-fractionation EBRT (50.4 Gy) and escalating weekly doses of gemcitabine (300 mg/m2, 400 mg/m2, 500 mg/m2) (43). Eight of 15 patients were hospitalized after chemoradiation. Pancreaticoduodenectomy was completed in 8 patients, yet 6 of these 8 patients were found to have positive resection margins following pathologic analysis of the resected specimen.