الفهرس 
Epidemiology and pathogenesisOnly 14 pages are availabe for public view
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Abstract
A
dvanced NSCLC encompasses metastatic disease (Stage IV) as well as locally advanced disease (Stage IIIB) that due to tumor or patient characteristics cannot be approached with curative intent .(4) The standard treatment of Advanced stage NSCLC is platinum doublet chemotherapy, gemcitabine and cisplatin combination is considered one of the most effective for NSCLC.
Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2’,2’-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2’,2’-difluoro-deoxyuridine, which is largely excreted into the urine.
Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m2 per minute was associated with a higher intracellular accumulation of dFdCTP, and a higher response rate than with the standard 30-minute infusion of gemcitabine . The explanation for this phenomenon lies in the saturation of deoxycytidine kinase which occurs after short infusion at conventional doses. This enzyme is needed to convert gemcitabine into its active form gemcitabine triphosphate. While short infusion leaves most of the drug unmetabolized, prolonged infusion results in a higher intracellular concentration of the active metabolite, thus enhancing the agent’s efficacy.
This is a phase III prospective clinical trial conducted in Clinical Oncology and Nuclear Medicine Department, Ain Shams University Hospitals during the period from May 2009 to May 2011inclusive, comparing the efficacy and safety of low dose prolonged infusion with the standard dose rate infusion , with a median follow up period of 13 months ranging from 3 to 24months. The study included sixty eligible chemonaive patients with metastatic non small cell lung cancer.Patients were divided into 2 arms, each arm composed of 30 patients.
All eligible patients fulfilling the inclusion criteria and after pretreatment assessments were divided into two groups, ARM A received gemcitabine 1000 mg/m2 over 30 minutes on days 1 & 8 plus Cisplatin 75 mg/m2 on day 2, ARM B received gemcitabine 250 mg/m2 over 6 hours on days 1 & 8 plus Cisplatin 75 mg/m2 on day 2, cycle was repeated every 3 weeks in both groups of patients. Assessment of the response was done according to the WHO criteria every 2 cycles and the toxicity was assessed using NCI criteria for common toxicities every cycle.
Among the group who received standard dose gemcitabine and cisplatin (ARM A), the overall response rate was 46.6% where only 1 patient (3.3%) achieved complete response, 13 patients (43.3 %) achieved partial response, 12 patients (40%) were stationary, 4 patients (13.3%) progressed. The median time to disease progression was 7 months. Median survival time was 12 months. The survival rate at 12 month was 83.4% and at 18 months 34.2% and 24 months was 10.5%. Hematologic toxicity was mild, with grade 3 hematologic toxicities consisted of neutropenia in 26.7 % of patients, thrombocytopenia in 12.5 % and anemia in 20 % of patients, there was no grade IV toxicity, while the non hematological toxicity consisted of grade III nausea and vomiting in 35.7 % of patients.grade I and II mucositis in 10 % of patients , grade I and II diarrhea in 10 % of patients, grade I and II alopecia in 33.3 % of patients, grade I hepatic toxicity in 3.3 % of patients, grade I and II renal toxicity in 6.7 % of patients, grade I and II fatigue in 43.3 % of patients, grade I and II neurosensory in 30 % of patients, There was no treatment related mortality.
While among the group who received low dose gemcitabine , and cisplatin (ARM B), the overall response rate was 43.3% %, where only 1 patient ( 3.3%) achieved complete response, 12 patients (40%) achieved partial response, 13 patients (43.3%) were stationary, 4 patients (13.3%) progressed The median time to disease progression was 6 months. Median survival time was 11 months.The survival rate at 12 month was 63.4% and at 18 months 22.6% and 24 months was 8.7%. Hematologic toxicity was mild, with grade 3 hematologic toxicities consisted of neutropenia in 20% of patients, thrombocytopenia in 7.7 % and anemia in 8.7 % of patients with no grade IV toxicity while the non hematological toxicity consisted of grade III nausea and vomiting in 34.6 % of patients. grade I and II mucositis in 16.7 % of patients, grade I diarrhea in 3.3 % of patients, grade I and II alopecia in 46.6 % of patients, grade I hepatic toxicity in 10 % of patients , grade I and II renal toxicity in 13.3 % of patients, grade I and II fatigue in 33.3 % of patients, grade I and II neurosensory in 23.3 % of patients, There was no treatment related mortality.
The response and the toxicities of the protocol matched the results of other first line chemotherapeutic combinations which encourage direct comparison with phase III head to head trials.