GI Unit, London and Surrey, Royal Marsden Hospital, UK (E-mail: dcunn@icr.ac.uk)
Some 5 years ago we reviewed the literature on the treatment of advanced and metastatic pancreatic cancer. At that time gemcitabine had recently emerged as the new standard treatment for advanced disease based on a relatively small North American randomised trial, which compared gemcitabine to 5-fluorouracil (5-FU) given by bolus injection. Gemcitabine produced superior response rate, survival and clinical benefit [1], and rapidly gained widespread use in North America, but the uptake in Europe was slowerthe trial had been criticised for the suboptimal schedule of 5-FU. However, the agent gradually gained clinical acceptance in Europe and with the publication of the National Institute of Clinical Excellence (NICE) guidelines supporting gemcitabine in June 2001, the UK followed suit. Moreover, during these 5 years gemcitabine survived several randomised trials. It was shown to be superior to the matrix metalloproteinase inhibitors (Bay-129566 and marimastat) [2, 3], and in a ECOG trial the addition of bolus 5-FU to gemcitabine was shown to be no better than gemcitabine alone [4].
Indeed, the ECOG trial might have implied that the use of 5-FU was now redundant in advanced pancreatic cancernot so. In this issue of Annals of Oncology, Ducreux et al. report the results of a randomised trial in advanced pancreatic cancer comparing bolus 5-FU with the combination of infused 5-FU and cisplatin [5]. They demonstrated superior response rate (12% versus 0%) and 1-year progression-free survival (10% versus 0%) for the combination arm, although overall survival was equivalent in both arms. This trial once again confirmed the lack of efficacy of bolus 5-FU but did show that infused 5-FU combined with cisplatin has modest activity, but not without significant toxicity. Was this due to the different schedule of 5-FU or the addition of cisplatin? A recently published randomised trial has shown a 1-year survival rate of 23% for patients with advanced pancreatic cancer when treated with 5-FU given by protracted venous infusion (PVI) (Table 1). In this particular trial mitomycin C increased response rate but not progression-free survival or survival. However, the same group have also evaluated PVI 5-FU (300 mg/m2) and cisplatin (60 mg/m2 every 21 days), and reported less toxicity than Ducreux et al. [6]. Overall, these data are encouraging and support a continuing role for 5-FU in pancreatic cancer treatmentreflected in the recent trials, which have evaluated gemcitabine in combination with the oral fluoropyrimidine, capecitabine.
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With the use of newer drugs (such as oxaliplatin, irinotecan and docetaxel) in the treatment of advanced pancreatic cancer, patients with good performance status whose disease is refractory to gemcitabine now have the option of second-line chemotherapy. In the studies reported to date, median survival from commencing salvage treatment ranges from 4 to 5.6 monthsa significant time period for a group of patients with a poor prognosis [9, 10].
When deciding on treatment for these patients potential toxicity is particularly important as patients usually present with multiple symptoms. Patients with locally advanced disease are frequently treated with chemoradiation which can be associated with marked toxicity [11]. Staging of these patients is often inadequate, many patients will have undetected peritoneal metastases at the time of diagnosis and therefore may be subjected to unnecessary treatment-related morbidity. Conventional computed tomography scans are poor at detecting peritoneal metastases, thus multimodality staging with FDG-positron emission tomography or laparoscopic surgery may provide more accurate information in this group of patients.
Our understanding of the molecular biology of pancreatic cancer continues to improve, opening up new avenues for treatment. The matrix metalloproteinase inhibitors (Bay-129566 and marimastat) have been shown to be inferior to gemcitabine in the treatment of metastatic pancreatic cancer in large phase III studies [2, 3]. However, their mechanism of action is to retard the development of metastatic disease and thus their full potential may be realised in the adjuvant and locally advanced setting. Cetuximab (IMC-225) is the first chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR) to be tested in previously untreated advanced pancreatic cancer patients in combination with gemcitabine. Early results are promising, with a phase II study reporting a partial response rate of 12% after two courses of treatment and a median time to progression of 16 weeks [12]. HER-2 is also overexpressed in pancreatic cancer [13], and trastuzumab, the humanised monoclonal antibody binding to this receptor, is undergoing evaluation. A phase II study demonstrated a partial response rate of 22% when combined with gemcitabine as first-line treatment [14]. Erlotinib (Tarceva OSI774) is an orally active, reversible selective EGFR tyrosine kinase receptor inhibitor. It is currently being evaluated in combination with gemcitabine in a phase III study with single-agent gemcitabine as the control arm. Large randomised studies to evaluate the role of trastuzumab, cetuximab (IMC-225) and erlotinib in this setting are awaited, but these new targets offer hope in a disease that has been considered chemoresistant for many years.
In the last 5 years there has been some real progress in the treatment of pancreatic cancer, but more importantly, the next 5 years hold much more promise than at probably any other time in the history of oncology, with the opportunity to improve the results from conventional cytotoxic drugs and to integrate the new targeted therapies in this disease. Enthusiasm is high and expectation greater than ever.
S. Rao & D. Cunningham
GI Unit, London and Surrey, Royal Marsden Hospital, UK(E-mail:dcunn{at}icr.ac.uk)
References
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