Gemcitabine/5-flourouracil/leucovorin for the treatment of advanced pancreatic carcinoma.

BACKGROUND AND OBJECTIVE: The response rate and median survival with gemcitabine monotherapy, although considered the standard treatment for inoperable and metastatic pancreatic cancer, is relatively poor. We tested the efficacy and toxicity of a chemotherapy protocol consisting of gemcitabine, 5-fluorouracil (5-FU) and leucovorin in patients with inoperable or metastatic pancreatic cancer, which was shown to improve median survival in a small phase II trial. PATIENTS AND METHODS: Patients older than 18 years of age with histologically or cytologically confirmed adenocarcinoma of the pancreas and bidimensionally measurable disease, and who were chemotherapy- and radiotherapy-naïve, were treated with a chemotherapy protocol consisting of gemcitabine 1250 mg/m2 on day 1, 5-FU 450 mg/m2 and leucovorin 100 mg/m2 on days 1-3. The treatment was repeated every 2 weeks. RESULTS: In an-intention-to-treat analysis, of 37 patients with pancreatic cancer (27 males, 10 females) (67.6% stage IVb) there were 7 (18.9%) objective partial responses (95% confidence interval, 8.33% to 29), 14 (37.8%) patients had stable disease and 16 (43.2%) had progressive disease. The median response time was 3 months (range, 1.5 to 7.0 months). Median overall survival time was 6.5 months (range, 1.0 to 15.5 months). The response to chemotherapy was not different between males and females (P = .971). No grade III/IV toxicities were seen. CONCLUSION: Despite our poor survival data, the combination of gemcitabine with 5-/FU and leucovorin is an active and well-tolerated regimen in patients with pancreatic cancer that merits further evaluation in prospective randomized studies. This combination may be considered a valuable alternative to gemcitabine alone.

Induction chemotherapy with the TIP regimen (paclitaxel/ifosfamide/cisplatin) in stage III non-small cell lung cancer.

Induction chemotherapy may improve clinical outcome of locally advanced non-small cell lung cancer (NSCLC). To further pursue this, the Austrian Association for the Study of Lung Cancer (AASLC) performed a multi-center phase II trial with TIP induction chemotherapy (Taxol 175 mg/m2 over 3h on day 1, ifosfamide 1000 mg/m2 daily on days 1-3, cisplatin 60 mg/m2 on day 1, and prophylactic filgrastim 5 microg/kg daily on days 4-13). Treatment cycles were repeated every 3 weeks for 3 cycles. Then patients were re-staged and selected for local treatment. Forty-seven patients (33 male, 14 female; median age 58 years, range 36-78; 22 cIIIA, 25 cIIIB; 26 adenocarcinomas, 14 squamous cell carcinomas, 4 large cell carcinomas, 3 undifferentiated carcinomas) were included in this trial. Forty-five patients were evaluable for response and toxicity. An overall response rate of 43% (complete remission 4.5% and partial remission 38%) was achieved. Stable disease and progressive disease were seen in 38 and 15% of the patients, respectively. Down-staging occurred in 36% of the patients. The toxicities of the chemotherapy were mild and, in particular, no severe hematotoxicity was observed. Surgery was performed in 24 (51%) patients and resulted in complete tumor resection in 19 patients. Twenty-four patients received thoracic radiotherapy, 10 patients after surgery. Median survival was 10.3 months for the total population, 13.5 months for patients with cIIIA and 10 months for patients with clinical cIIIB. Survival was longer for patients with down-staging as compared to those without (median not reached versus 10 months, p=0.005) and for patients with complete tumor resection as compared to the remaining patients (27 months versus 10 months, p=0.05). In conclusion, the TIP regimen shows activity and good tolerance as induction chemotherapy in patients with locally advanced NSCLC.

Ligation of CD8alpha on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity.

It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8- counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8- NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8alpha+ cells after lysis of the same targets. We report that cross-linking of the CD8alpha chains on NK cells induces rapid rises in intracellular Ca2+ and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca2+ ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8alpha+ NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8- subset, CD8alpha+ NK cells are capable of sequential lysis of multiple target cells.