Chemotherapy prolongs survival in inoperable pancreatic carcinoma

Palmer, K R; Kerr, Michael Patrick; Knowles, Gillian; Cull, Ann; Carter, D. C.; Leonard, Robert

doi:10.1002/bjs.1800810629

Cited by 242 publications

(96 citation statements)

References 13 publications

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“…Most of the incorporated EPA appears to remain in the phospholipid component of cell membranes (Brown and Subbaiah, 1994), although the cytoplasmic lipid accumulation observed in the present study may suggest that other mechanisms are also important. However, it has been shown that the relative quantity of polyunsaturated fatty acids in the cell membrane may play an important role in regulation of proliferation and cellular functions (Brown and Subbaiah, 1994;Pan et al, 1990;Bandyophadhyay et al, 1993). It is possible that EPA may alter the microenvironment of surface receptors or signalling proteins in the cell membrane, thereby inducing inappropriate signalling moieties and initiating cell cycle arrest and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, surgical resection is rarely feasible, since most patients present with advanced inoperable disease. Although some groups have demonstrated slightly improved survival with conventional cytotoxic chemotherapy (Palmer et al, 1994), there is, at present, no effective treatment for advanced pancreatic cancer. There is, therefore, a need to develop selective and relatively non-toxic treatment regimens directed at reducing the morbidity and mortality associated with pancreatic cancer.…”

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confidence: 99%

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Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro

Lai

Ross²,

Fearon³

et al. 1996

Br J Cancer

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Summary Eicosapentaenoic acid (EPA) has been shown to have an inhibitory effect on the growth of several pancreatic cancer cell lines in vitro. This study investigates the mechanism of growth inhibition and cytotoxicity of EPA on the pancreatic cancer cell line MIA PaCa-2. Cells were analysed for cell count, viability, cell cycle distribution and ultrastructural changes. There was a time-and dose-dependent decrease in cell count and viability in cultures of pancreatic cancer cells supplemented with EPA. Flow cytometric DNA anlaysis of MIA PaCa-2 cells incubated with EPA demonstrated the presence of sub G1 populations corresponding to the presence of apoptotic cells and the blockade of cell cycle progression in S-phase and G2/M-phase. The presence of apoptosis in EPA-supplemented cultures was further confirmed by DNA fragmentation and ultrastructural changes associated with apoptosis. Therefore, we conclude that EPA mediates its effect on the pancreatic cancer cell line MIA PaCa-2, at least in part, via cell cycle arrest and the induction of apoptosis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro

Lai

Ross²,

Fearon³

et al. 1996

Br J Cancer

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“…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).…”

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confidence: 99%

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

et al. 2002

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Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor. Recent advances in conventional chemotherapy and the development of novel 'molecular' treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies. This randomised study in pancreatic cancer compares marimastat (orally administered matrix metalloproteinase inhibitor) in combination with gemcitabine to gemcitabine alone. Two hundred and thirty-nine patients with unresectable pancreatic cancer were randomised to receive gemcitabine (1000 mg m 72 ) in combination with either marimastat or placebo. The primary end-point was survival. Objective tumour response and duration of response, time to treatment failure and disease progression, quality of life and safety were also assessed. There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo (P=0.95 log-rank test). Median survival times were 165.5 and 164 days and 1-year survival was 18% and 17% respectively. There were no significant differences in overall response rates (11 and 16% respectively), progression-free survival (P=0.68 log-rank test) or time to treatment failure (P=0.70 log-rank test) between the treatment arms. The gemcitabine and marimastat combination was well tolerated with only 2.5% of patients withdrawn due to presumed marimastat toxicity. Grade 3 or 4 musculoskeletal toxicities were reported in only 4% of the marimastat treated patients, although 59% of marimastat treated patients reported some musculoskeletal events. The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer. The combination of marimastat with gemcitabine was well tolerated. Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified.

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“…Nevertheless, palliative chemotherapy can improve overall survival compared with no treatment without impairing quality of life (Mallinson et al, 1980;Leonard et al, 1992;Palmer et al, 1994). Objective response rates remain low with most single-agent chemotherapy including 21 -26% with 5FU (Carter, 1975;Moertel, 1976), 26% with ifosfamide (Bernard et al, 1986), 22% with epirubicin (Wils et al, 1985) and 21% with cisplatin (Wils et al, 1993).…”

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A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

et al. 2002

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Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo . Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10–15 μg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82–532 days (median=168 days). The time to treatment failure ( n =36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states. British Journal of Cancer (2002) 86 , 680–685. DOI: 10.1038/sj/bjc/6600162 www.bjcancer.com © 2002 Cancer Research UK

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Chemotherapy prolongs survival in inoperable pancreatic carcinoma

Cited by 242 publications

References 13 publications

Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro

Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro

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

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

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