Pancreatic cancer is the fifth most common cause of cancer death in Japan. The prognosis is extremely poor because it is difficult to detect this disease in the early stage and also the postoperative incidence of recurrence is still high, and we have not had any effective treatment for inoperable patients. Recently, the chemoradiotherapy has been regarded as one of the standard therapy for locally advanced pancreatic cancer and it has improved the survival and presented a clinical benefit. In the early 1980s, fluorouracil-based concomitant chemoradiotherapy was shown to be better than radiotherapy alone for patients with locally advanced pancreatic cancer. Gemcitabine has improved the outcome of patients with advanced disease by improving survival with a clinical benefit. Gemcitabine also has been shown to be a potent radiosensitizer both in vivo and in vitro. The vast majority of the reported phase I-III clinical trials have used gemcitabine as a single agent given weekly in a single dose (i.e. 250 mg/m2), and there is no consensus of the protocol of the administration of gemcitabine. Several preclinical data including animal studies would suggest that maximum radiation sensitization with gemcitabine is observed at a lower dose administered twice weekly.
A research article to be published on September 14, 2008 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. IGARASHI from Pancreatic Diseases Branch of Kyushu University in Japan focused on the maximum radiation sensitization with gemcitabine. They performed the retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2. After that, maintenance systemic chemotherapy with gemcitabine at a dose of 1000 mg/m2 was administered weekly for 3 weeks with 1-week rest until disease progression or unacceptable toxicity. Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled. Three of those patients could not continue with the therapy, because one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis in an early stage of therapy. The median survival was 15.0 months and the overall 1-year survival rate was 60%, while the median progression- free survival was 8.0 months. The subgroup which showed the reduction of tumor maker more than 50%, had a tendency for a better prognosis, however other parameters including age, gender and performance status did not correlate with survival. The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 months and 27.7 months, respectively.
Although this study using a twice weekly gemcitabine infusion schedule for locally advanced pancreatic cancer was not a controlled study, the results of the median survival time, median disease free survival time and overall 1-year survival rate was found to be preferable compared to previous studies.
Hugut et al (J Clin Oncol 2007; 25: 326-331) discussed that, an important concern about administrating chemoradiotherapy as first-line treatment in patients with locally advanced pancreatic cancer was that approximately 30% of them had occult metastatic disease at diagnosis and thus they would clearly not benefit from this locoregional treatment. Furthermore, other investigator demonstrated that a fraction of patients with locally advanced pancreatic cancer developed metastases within a few weeks and died very quickly despite the type of treatment. In this study, the patients who developed liver metastasis had a worse prognosis, which might owe to the mis-diagnosis of the staging of the disease at the initiation of the therapy, because of failure to detect micrometastasis by conventional imaging modalities. In this situation, another strategy for the chemoradiotherapy for locally advanced pancreatic cancer might be required, such as one in which the patients receive one or two cycles of systemic chemotherapy using gemcitabine at a dose of 1,000 mg/m2 weekly for 3 weeks with 1-week rest, and then re-evaluated the staging of the disease, initiating the chemoradiotherapy under the protocol in this study. Further investigations are required in the near future.