INTRAOPERATIVE RADIATION THERAPY 

Additional boost irradiation can be given to an unresectable pancreatic cancer during surgery with EB-IORT. The use of EB-IORT with or without EBRT in patients with locally advanced pancreatic cancer has been extensively studied. The use of both EB-IORT and EBRT has been reported to result in improved survival rates compared with surgical bypass alone or EB-IORT alone. This combined therapy may reduce morbidity compared with EB-IORT alone because smaller EB-IORT doses can be used; high single doses of EB-IORT (more than 30 Gy) can result in duodenal ulceration, perforation, or hematochezia from radiation duodenitits. In the United States, several institutions have used EB-IORT at doses between 10 and 20 Gy in combination with preoperative or postoperative EBRT given at doses of 45 to 50 Gy over 5 to 6 weeks. Most studies used EB-IORT at the time of surgical exploration, and in patients with no metastatic disease, treatment was consolidated with postoperative EBRT; median survival times have ranged from 12 to 15 months. Rates of local tumor control appear to be superior to those of historic controls treated with EBRT with or without 5-FU. In a recent report from Mohiuddin and colleagues, 49 patients received EB-IORT (10 to 20 Gy) followed by EBRT (40 to 50 Gy) and systemic chemotherapy (5-FU, 450 mg/m2 ; leucovorin, 100 mg/m2 given every 10 days) given during EBRT and continued for 2 years or until evidence of disease progression. Median survival was 16 months, and the dominant site of recurrent disease was the liver. The extent to which patient selection affected outcome in this and other studies of combined EB-IORT and chemoradiation is difficult to determine.

TREATMENT DECISIONS: LOCALLY ADVANCED, NONMETASTATIC DISEASE

Patients with clear evidence of encasement of the celiac axis or SMA or occlusion of the SMPV confluence on contrast-enhanced, helical CT do not require laparotomy to confirm that the tumor is unresectable; cytologic confirmation of malignancy can be achieved with CT-guided FNA. This fundamental advance in the pretreatment diagnosis of pancreatic tumors can improve the quality of patient survival and reduce health care costs by avoiding the morbidity and prolonged recovery associated with palliative pancreatic cancer surgery. Published data have demonstrated increased length of survival for patients treated with chemoradiation, but this benefit is limited largely to patients with higher performance status. Therefore, a program of 5-FU-based chemoradiation is justified in fully ambulatory patients with locally advanced disease who have minimal symptoms. Systemic therapy with gemcitabine also represents a reasonable alternative in these patients. For patients with poor performance status, chemoradiation is probably not indicated. Current pharmacologic and interventional techniques for pain control, including percutaneous injection of alcohol into the celiac plexus, have proven highly successful in patients with pancreatic cancer. Furthermore, adequate pain control improves performance status and quality of life, which may translate into increased length of life. The limited therapeutic options available for patients with locally advanced disease and the modest impact of current treatments on survival rates provide the rationale for the entry of patients into trials examining novel systemic agents.

TREATMENT DECISIONS: METASTATIC DISEASE

The complex pathophysiologic abnormalities accompanying metastatic pancreatic cancer often make specific treatment decisions extremely difficult. Many patients present to the medical oncologist or surgeon with profound debilitation, severe pain, and extensive metastatic disease. For these patients, intervention with chemotherapy is unlikely to result in significant improvements in quality of life or survival, and the toxic effects of chemotherapy may create additional complications. Management with supportive care or nontoxic hormonal approaches may be the optimal strategies for these patients.

For patients with metastatic pancreatic cancer who present with a good performance status, treatment with systemic chemotherapy is appropriate. In view of the limited impact of the currently available agents on survival, continued enrollment of patients in phase II trials of new agents or combinations is essential. In the absence of access to a phase II trial, treatment with gemcitabine appears to be the evolving standard. However, it must be recognized that the primary impact of gemcitabine is on quality of life; therefore, continued evaluation of novel agents, especially those targeted against specific molecular events important in the pathogenesis of pancreatic cancer, is crucial. As our understanding of the molecular and biochemical basis of pancreatic cancer expands, we will enter a new era in which treatments are tailored to interact with the specific molecular and biochemical targets thought to be important in the development or maintenance of neoplasia.