Phase II study of gemcitabine in patients with advanced pancreatic cancer

Abstract

Summary The efficacy and safety of gemcitabine at a starting dose of 800 mg m2 administered once a week for 3 weeks with 1 week's rest was investigated in chemonaive patients with advanced and/or metastatic pancreatic cancer. Of 34 patients, 32 were evaluable for efficacy, 20 patients had metastatic stage IV disease, 25 had a performance status of I and 26 (76%) patients has significant pain on presentation. All responses were independently validated by an external oncology review board: two patients achieved a partial response that lasted 5.8 and 5.2 months (6.3%) and six patients were stable for at least 4 weeks. The median duration of survival for evaluable patients was 6.3 months (range 1.6-19.2 months). The tumour markers, CEA, CA 19-9 and CA 195 were serially measured in 16 patients. There was a good correlation with tumour response when all three markers were significantly decreased. In 4 of 16 patients, tumour marker levels decreased by > 60%, including the two responders, one patient who survived for 12 months and one patient who showed objective tumour shrinkage but was deemed ineligible for response evaluation because the disease was considered not to be bidimensionally measurable. Symptomatic benefits included improvement in performance status (17.2%), analgesic requirement (7.4%), pain score (28.6%) and nausea (27.3%). The mean number of cycles administered was 2.5 and the mean dosage received was 890 mg m2 per injection. Seventy-four per cent of dose administrations were given on schedule. Toxicity, particularly haematological toxicity, reported as the maximum WHO grade experienced by patients was mild. Infective episodes were rare and limited to WHO grade 2 (6.7%). Nausea and vomitimg was generally modest (WHO grade 3, 26.7%). Other side-effects included mild transient flu-like symptoms (seven patients) and peripheral oedema (three patients), which was not associated with abnormal cardiac hepatic or renal function. Gemcitabine has modest activity in pancreatic cancer, a limited positive improvement on a range of patient benefit parameters and has a mild toxicity profile. For these reasons and because of its novel mode of action, gemcitabine warrants further investigation in combination studies in pancreatic cancer.

Weekly gemcitabine plus Epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study

“…Recently, there has been renewed interest in single -agent chemotherapy with the advent of novel agents such as irinotecan (response rate 11%) (Sakata et al, 1993) and docetaxel (response rate 20%) (Androulakis et al, 1999). Single-agent GEM has also been recently investigated for activity as well as toxicity in advanced pancreatic cancer by Casper et al, 1994 andCarmichael et al, 1996, who reported modest objective response rates of 6.3 -11% and median survivals of 5.6 -6.3 months; however, the symptomatic improvements were greater than the objective tumour response rates would suggest. Consequently, the National Cancer Institute and the Food and Drug Administration (USA) have accepted that the relief of tumourrelated symptoms is itself a noteworthy goal of carcinoma treatment (O'Shaughnessy et al, 1991).…”

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

“…Several studies have reported encouraging results with single chemotherapy agents or combination treatments (Mallinson et al, 1980;Casper et al, 1994;Palmer et al, 1994;Carmichael et al, 1995;Burris et al, 1997) and gemcitabine has been compared to 5-fluorouracil (5-FU) in a phase III study in patients with advanced pancreatic cancer (Burris et al, 1997). The results of this study suggested that patients receiving gemcitabine had both an improved survival and patient benefit compared to those patients receiving 5-FU and these data and data from several other studies have led to the widespread acceptance of gemcitabine as first-line therapy in patients with advanced pancreatic cancer Carmichael et al, 1995;Rothenberg et al, 1996;Burris et al, 1997;Storniolo et al, 1999).…”

Preclinical relevance of dosing time for the therapeutic index of gemcitabine–cisplatin

“…Gemcitabine undergoes intracellular phosphorylation to the active metabolites gemcitabine diphosphate and gemcitabine triphosphate, leading to inhibition of ribonucleotide reductase and incorporation of gemcitabine triphosphate into DNA and RNA (Xu and Plunkett, 1992;Ruiz van Haperen et al, 1993). It is active against non-small-cell lung cancer, pancreatic cancer, breast cancer and ovarian cancer (Abratt et al, 1994;Lund et al, 1994;Carmichael et al, 1995Carmichael et al, , 1996. A review of gemcitabine safety profile establishes this drug as a relatively safe antimetabolite, with adverse events that generally are manageable and reversible, rarely leading to discontinuation of the drug.…”