Pancreatic cancer gemcitabine

Erlotinib has been approved by the FDA for second- or third-line treatment of NSCLC [45], and in combination with gemcitabine as first-hne therapy for pancreatic cancer [46]. Since the majority of human studies with erlotinib have been in NSCLC, the clinical discussion will focus on this indication. When dosed oraUy once a day at 150mg/day in an uncontrolled phase II study, erlotinib resulted in a 12% objective response rate in second-or third-hne NSCLC patients [47,48]. In first-hne NSCLC, phase III studies of standard-of-care with or without erlotinib failed to show a chnical benefit in objective response rate, time to progression, or survival for the erlotinib-treated group. However, in a large placebo-controlled phase III trial, erlotinib provided a clear survival benefit as single agent in second- or third-hne treatment of NSCLC, which subsequently led to FDA approval [45,49]. In that trial, patients were randomized to receive erlotinib in addition to supportive... 

The treatment of pancreatic cancer continues to be challenging. Standard treatment with 5-FU-based regimens and radiation has resulted in 5-yr survival rates of 15-20%. In locally advanced and metastatic patients, the median survival is less than 10 mo. As such, investigators have tried to improve outcomes by incorporating novel agents like gemcitabine into therapy (Table 5). 

Gy of radiation to the pancreas was tolerable in pancreatic cancer patients with a 20% response rate in 15 evaluable patients. Three out of eight patients with a minimum of 12 mo follow up were alive (65). Based on these data, Cancer and Leukemia Group B (CALGB) conducted a phase II trial to examine the efficacy of concurrent twice-weekly Gemcitabine (40 mg/m2) and radiation (50.4 Gy) treatment regimen in patients with locally advanced pancreatic cancer. The preliminary result showed 55% of the... 

Wilkowski R, Heinemann V, Rau H, et al. Radiochemotherapy including gemcitabine and 5-FU for treatment of locally advanced pancreatic cancer. Proc Am Soc Clin Oncol 2000 19 276a. 

McGinn CJ, Smith DC, Szarka CE, et al. A phase I study of gemcitabine in combination with radiation therapy inpatients with localized, unresectable pancreatic cancer. Proc Am Soc Clin Oncol 1998 17 264a. 

S af ar AM, Altamiro PS, Recht A, et al. Phase I trial of gemcitabine, cisplatin and external beam radiation therapy for pancreatic cancer. Proc Am Soc Clin Oncol 1999 18 227a. 

Blackstock AW, Bernard S A, Richards F, et al. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. JCO 1999 17 2208-2212. 

Gemcitabine, a new pyrimidine antimetabolite, is of substantial interest as a radiosensitizer in the treatment of pancreatic cancer. An ongoing multi-institutional Phase II study of preoperative EBRT and concomitant gemcitabine therapy for resectable adenocarcinoma will provide useful information (57-60). 

Hidalgo M, et al. Phase I-II study of gemcitabine and fluorouracil as a continuous infusion in patients with pancreatic cancer. J Clin Oncol 1999 17(2) 585—592. 

There is no proof currently that MMPIs as a class will prolong the survival of patients with cancer. Currently, three randomized trials of MMPIs have reported survival data BAY 12-9566 vs gemcitabine in locally advanced or metastatic pancreatic cancer (10), marimastat vs gemcitabine in locally advanced or metastatic pancreatic cancer (11), and marimastat vs placebo in locally advanced or metastatic gastric cancer (12). 

Moore MJ, Hamm P, Eisenberg P, Dagenais M, Hagan K, Fields A, et al. A comparison between gemcitabine (GEM) and the matrix metalloproteinase (MMP) inhibitor BAY 12-9566 (9566) inpatients (pts) with advanced pancreatic cancer. ProcAm Soc Clin Oncol 2000 19 240a (abstract). 

Rosemurgy A, Buckets J, Charnley R. A randomized study comparing marimastat to gemcitabine as first line therapy in patients with non-resectable pancreatic cancer. ProcAm Assoc Cancer Res 1999 18 261a (abstract). 

Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer. JAMA 2007 297 267-77. 

Gemcitabine (Gemzar), an antimetabolite, undergoes metabolic activation to difluorodeoxycytidine triphosphate, which interferes with DNA synthesis and repair, ft is the single most active agent for the treatment of metastatic pancreatic cancer, and it is used as a first-line treatment for both pancreatic and small cell lung cancer. It is administered by intravenous infusion. The dose-limiting toxicity is bone marrow suppression. 

Pharmacogenomic studies have led to many results that can be used to tailor therapy for cancer patients. Many reports have showed the identification of proteins concerned with drug-resistance proteomically (40,41,42,43,44). In fact, we identified HSP27 as a protein related to resistance to gemcitabine, which is the only effective anti-cancer drug against pancreatic cancer (45,46)... 

Mori-Iwamoto S, Kuramitsu Y, Ryozawa S et al. A proteomie profiling of gemcitabine resistance in pancreatic cancer cell lines. Molecular Medicine Reports 2008 1 429 34. 

Gemcitabine Inhibits DNA synthesis and repair inhibits ribonucleotide reductase with reduced formation of dNTPs incorporation of gemcitabine triphosphate into DNA resulting in inhibition of DNA synthesis and function Pancreatic cancer, bladder cancer, breast cancer, non-small cell lung cancer, ovarian cancer, non-Hodgkin s lymphoma, soft tissue sarcoma Nausea, vomiting, diarrhea, myelosuppression... 

Gemcitabine was initially approved for use in pancreatic cancer but is now widely used in the treatment of non-small cell lung cancer and bladder cancer. Myelosuppression is the principal dose-limiting toxicity. 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Van Cutsem, E., van de Velde, H., Karasek, P., Oettle, H., Vervenne, W.L., Szawlowski, A., Schoffski, P., Post, S., Verslype, C., Neumann, H., Safran, H., Humblet, Y., et al. (2004). Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22 1430-1438. 

Gemcitabine is an S-phase-specific pyrimidine nucleoside analogue of deoxycytidine (2, 2 -difluorodeoxycytidine) that is structurally similar to cytosine arabinoside. It has been used to treat metastatic urothelial carcinoma of the bladder, pancreatic cancer, and some other solid tumors. 

Thrombocytopenia also developed in a 72-year-old man who was treated with vancomycin for staphylococcal sepsis after treatment with gemcitabine for metastatic pancreatic cancer (53). On day 12 thrombocytopenia developed, reached a nadir on day 18 (13 x lO /l), and did not respond to platelet transfusions. Bone-marrow megakaryocjrtes were adequate. Platelet-associated IgG and IgM were increased. Vancomycin was withdrawn on day 28, with prompt recovery of the platelet count to 136 x lO /l in 10 days. 

Gemcitabine (Gemzar) Pancreatic cancer NSCLC breast cancer head and neck cancer bladder cancer testicular cancer ovarian cancers, HD... 

AD) as well as the treatment of several cancers, including colon and pancreatic cancers (in combination with agents such as gemcitabine and celebrex), as a chemopreventive agent against colorectal cancer, and in the prevention of oral mucositis in children receiving chemotherapy (http //www.clinicaltrials.gov). 

Modrak, D.E., Cardillo, T.M., Newsome, G.A., Goldenberg, D.M., and Gold, D.V. Synergistic interaction between sphingomyelin and gemcitabine potentiates ceramide-mediated apoptosis in pancreatic cancer. Cancer Res, 64, 2004, 8405-8410. 

Gemcitabine (2, 2 difluorodeoxycytidine dFdC), a di-fluoro analog of deoxycytidine, has become an important drug for patients with metastatic pancreatic cancer nonsmall-cell lung cancer and ovarian, bladder, esophageal, and head and neck cancer. 

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