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Byline: Emilio Esteban (1), Joaquin Fra (1), Marian Sala (1), Juan Carrasco (1), Norberto Corral (1), Jose Maria Vieitez (1), Enrique Estrada (1), Isabel Palacio (1), Jose Mari Buesa (1), Angel J. Lacave (1) Abstract: Purpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m.sup.2 andvinorelbine 25 mg/m.sup.2 intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m.sup.2 and 5 mg/m.sup.2,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m.sup.2 on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m.sup.2).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000--1250/25 mg/m.sup.2)followed (24 hours later) by cisplatin50 mg/m.sup.2. Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5--12) and 11 months (95 % CI:9--13), respectively. World HealthOrganization toxicity aY= grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and aY= grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting(aY= grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000--1250 mg/m plus vinorelbine25 mg/m.sup.2 on days 1 and 8, followed bycisplatin 50 mg/m.sup.2 24 hours later, issafe for outpatient administration andactive in patients with NSCLC. Author Affiliation: (1) Servicio de Oncologia Medica, Hospital Central de Asturias, Oviedo, Spain Article History: Registration Date: 10/10/2004

Background: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated the immunohistochemical (IHC) expression of p-IGF1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS). Methods: Ninety-two advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF1R system, we have used an antibody (anti-pY1316) that specifically recognizes the active phosphorylated form of the IGF1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9, 11, 13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirectional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p < 0.10 and criterion to keep the variable in the model of p < 0.05. PFS was computed as the date of imatinib initiation to progression or death. Overall survival was defined as the time from imatinib initiation to death. Results: Phospho-IGF1R was expressed only in 9 % (2/22) of cases without KIT mutation. MMP3 expression was detected in 2/5 patients (40 %) with PDGFRA mutation, 1/16 patients (6 %) with WT genotype and 7/71 patients (10 %) of KIT mutant patients. At univariate analysis KIT exon 11/13 mutation had better PFS than patients with exon 9 mutation, PDGFRA mutation or WT genotype (p = 0.021; HR: 0.46; 95 %CI (0.28-0.76). Less than 24 months disease free-interval (HR 24.2, 95 % CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95 % CI 2.5-15.9), extension of disease; >1 organ (HR 1.89; 95 % CI 1.03-3.4) and genotype analysis (HR 0.57, 95 % CI 0.37-0.97) but not immunophenotype analysis (HR 1.53; 95 % CI 0.76-3.06) were the strongest prognostic factors for PFS in the multivariate analysis. Conclusions: Our results do not support p-IGF-1R and MMP3 evaluation in non-selected GIST patients but evaluation of this immunophenotype in WT and mutant PDGFR mutation in larger group of GIST patients, deserve merits. [ABSTRACT FROM AUTHOR]