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Gemcitabine and Radiation

Cancer of the pancreas is the second most common gastrointestinal malignancy and the fourth leading cause of all cancer deaths. An estimated 26,300 new cases will be diagnosed in the United States in 1996. Despite all available treatment modalities, the median survival is a dismal three to four months, and only 3 percent of patients are alive five years from diagnosis.

Many factors contribute to the poor overall prognosis for these patients. The presenting symptoms of pancreatic cancer are vague, so most patients will present with locally advanced or distant metastatic disease. Similarly, the anatomy of the pancreas and aggressive nature of this tumor limit the potential for curative surgical resection. Lastly, severe cachexia, malnutrition and chronic pain associated with pancreatic cancer make any treatment approach difficult.

In the past decade, advances in operative techniques, postoperative support and the development of adjuvant chemoradio-therapy may have improved survival and decreased mortality for the few patients who present with localized tumors of the pancreas. With the introduction of more advanced diagnostic imaging and preoperative laparoscopy, surgeons now are better able to identify patients with resectable tumors. Despite improved resectability rates, a significant percent of patients will relapse. Thus, the median survival after curative resection remains a disappointing 20 months.

The high rate of relapse following curative resections identified a clear need for adjuvant strategies. The Gastrointestinal Tumor Study Group investigated the combination of radiation and 5-fluorouracil following curative resection of localized pancreatic tumors. In a small randomized trial, these investigators identified a survival benefit to the combined modality approach (21 vs. 10.9 months). This combined regimen has been adopted as the standard adjuvant therapy for resected pancreatic cancers.

The role of chemotherapy in the treatment of pancreatic cancers has been limited to the palliation of patients with advanced disease. Despite intense efforts, the use of chemotherapy remains unproven in this patient population. The identification of active chemotherapeutic agents is complicated by a variety of patient-related factors such as nutritional deficiencies, poor performance status and the absence of bidimensional measurable disease. These factors combine to make administrating aggressive chemotherapy difficult and hamper attempts to define and compare response rates.

Nevertheless, several chemotherapeutic agents are available with response rates of 15 percent or greater. Theseinclude 5-fluorouracil, mitomycin, ifos-famide and cisplatin. Lesser degrees of activity are seen with streptozotocin and doxorubicin. When used as single agents, these drugs produce few partial responses and virtually no complete responses.

Active single agents have been combined into several regimens including FAM [5-fluorouracil, doxorubicin (Adriamycin) and mitomycin C]; SMF (streptozotocin, mitomycin and 5-fluorouracil); FAMS (FAM plus streptozotocin); FAP (5-fluorouracil, doxorubincin and cisplatin); and FP (5-fluorouracil and cisplatin). In small single institution studies, encouraging response rates and median survivals have been reported with combination regimens, but these could not be reproduced by others.

Gemcitabine, an antimetabolite analogue of deoxycytidine, recently has demonstrated activity in pancreatic carcinoma. A prospective multicenter Phase II trial that examined clinical benefit criteria identified a 27 percent clinical benefit response in 63 patients treated. A randomized multicenter comparison of gemcitabine and 5-fluorouracil has been reported in abstract. In this trial, gemcitabine demonstrated a small but significant improvement in overall survival and increased the proportion of nine-month survivors from 6 percent with 5-fluorouracil to 24 percent. Gemcitabine recently has become available for the treatment of patients with advanced pancreatic cancer.

At this time, there is no standard effective single agent or combination chemotherapy program for unresectable adenocarcinoma of the pancreas. Efforts must continue to enroll patients in clinical trials investigating newer agents. A phase I trial of preoperative gemcitabine with radiation and postoperative gemcitabine for patients with localized, resectable pancreatic cancer.

Research done at Fox Chase Cancer Center suggests a potential benefit for neoadjuvant chemotherapy and radiation for localized pancreatic carcinoma. In a trial of 63 patients treated with preoperative 5-FU, mitomycin-C and radiation followed by surgery, a five-year survival rate of 40 percent was demonstrated for the 11 patients who had potentially curative resections. However, a confirmatory trial by the Eastern Cooperative Oncology Group demonstrated a median survival of only 22 months. Although both studies showed fewer locoregional recurrences, more than 75 percent developed distant metastases, underscoring the need for effective systemic adjuvant therapy.

As mentioned, gemcitabine (2',2'-difluorodeoxycytidine) appears to have activity in pancreatic cancer. The proposed mechanism of action involves its incorporation into DNA to terminate replication. Early studies in patients with lung cancer also have demonstrated significant radiation-enhancing properties of gemcitabine, which could prove useful in a combined-modality approach to pancreas cancer. Gemcitabine usually is well-tolerated, although significant toxicities have been reported including thrombocytopenia, leukopenia, asthenia, fever, nausea and vomiting.

Since gemcitabine has some activity in pancreas cancer and may enhance the activity of radiation, Ellis Fischel has joined its investigational resources with those of the Fox Chase Cancer Center and the University of Michigan to help identify the appropriate dosing, schedule and activity of gemcitabine with radiation therapy before attempted surgical resection. The proposed treatment will consist of six weeks of preoperative radiotherapy with weekly doses of gemcitabine. The dose of gemcitabine will be increased in successive patient groups until maximal tolerated dose is identified. Three to four weeks after completion of chemoradiation, the patients will be re-evaluated for surgery and resected if possible. Following surgery, adjuvant gemcitabine will be given for four months. It is hoped that 24 patients will be accrued to this protocol from the three institutions within two to three years.