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The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported.

Purpose: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non–small-cell lung cancer (NSCLC). Patients and Methods: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV–VI). Results: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV–VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV–VI, 27%; CG v GV–VI, P = .003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV–VI, 27%; P < .05); neutropenic fever (CG, 4%; CGV, 19%; GV–VI, 5%; P < .0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV–VI, 3%; P = .0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV–VI, 6%; P < .0001). Conclusion: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.

To assess, in a multicenter setting, the effectiveness of a combination of vinorelbine, ifosfamide and cisplatin in the treatment of non-small cell lung cancer, 123 patients (males=116) with a mean age of 60 years (range 27–75) with stage IIIb/IV non-small cell lung cancer (NSCLC) and performance status ≤2 were treated with vinorelbine (VNR; 25 mg/m 2 ) on days 1 and 8; ifosfamide (IFO; 3 g/m 2 ) on day 1; and cisplatin (CDDP; 80 mg/m 2 ) on day 1, in repeated cycles of 21 days. Response rates, overall patient survival and toxicity profiles of the three-drug combination were assessed. The number of evaluable patients was 112, with a total of 441 cycles administered (mean=3.6 cycles/patient). Dose intensities (mg/m 2 /week; calculated in patients who concluded the proposed treatment and expressed as mean, median, and standard deviation) were: VNR 13.65, 13.32, 4.7; IFO 918.88, 868.97, 258.1; CDDP 23, 24.68, 6.98. Response rates were: complete response=3 (2.4%); partial response=58 (47.2%%); stable disease=20 (16.3%). The most frequent toxic events were nausea and vomiting (G1=33%, G2=31%, G3=8%). Neutropenia was the dose limiting toxicity (G1=6%, G2=11%, G3=10%, G4=7%). Alopecia G3 was a common undesirable effect in all the patients. Time to progression was 296 days (95% confidence interval 261–332) and the mean survival time was 338 days (95% CI 301–374). We conclude that the described therapeutic schedule is effective with good survival rates and response ratios together with a good tolerance and an acceptable toxicity level.

Objective: This phase II trial was designed to assess the efficacy and toxicity profile of the combination of gemcitabine, ifosfamide and cisplatin (GIP) in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Patients and methods: Patients included in the study were those with surgically unresectable or metastatic NSCLC, with bidimensionally measurable disease, a Karnofsky performance status >60, and who had not received previous chemotherapy. Treatment consisted of 1000 mg/m 2 gemcitabine on days 1 and 8, 3 g/m 2 ifosfamide on day 1, and 50 mg/m 2 cisplatin on day 1, administered in 21-day cycles. A maximum of six cycles were administered. Results: Between March 1996 and December 1997, 60 patients were included in the study (37 stage III and 23 stage IV), of which 59 were evaluated for response. An objective response was obtained in 43% of patients (3% complete and 40% partial responses), whereas 22% had stable disease. The median survival time for the whole group was 52 weeks (65 weeks in patients with stage III, and 35 weeks in stage IV). The most frequent toxicity was haematological, 56% of patients presented grade 3 or 4 myelotoxicity in one of the cycles, although only seven episodes of febrile neutropenia were recorded in the 255 cycles administered. Conclusions: The GIP regimen attains response rates similar to those obtained with the gemcitabine plus cisplatin combination used in advanced NSCLC, and had an acceptable toxicity profile.

In a randomised, double-blind and parallel-design multicentre study, 282 chemotherapy-naive cancer patients received tropisetron 5 mg intravenously (i.v.) before high-dose cisplatin on day 1, and oral tropisetron 5 mg daily on days 2–6, in combination with either placebo ( n =143) or dexamethasone ( n =135), given i.v. on day 1 and orally on days 2–6. Complete protection from acute vomiting/nausea was achieved in 76.3%/79.3% of patients receiving the combination and in 55.2%/61.5% of those receiving tropisetron alone. Complete protection on days 2–6 from delayed vomiting/nausea was obtained in 60%/60% and 39.2%/40.6%, respectively. Tropisetron in combination with dexamethasone is safe and more effective than tropisetron alone in the prevention of both acute and delayed cisplatin-induced emesis.

Poor survival rates in extensive-stage small-cell lung cancer (SCLC) patients prompted us to evaluate a sequential dose-dense schedule of paclitaxel followed by topotecan.Forty-three patients with previously untreated, extensive-stage SCLC received three cycles of paclitaxel 250 mg/m(2) over 3 h every 14 days followed by three cycles of topotecan 2.5 mg/m(2) for 5 days every 21 days. Granulocyte colony-stimulating factor was given after every cycle. Patients progressing at any time and those not achieving complete response (CR) subsequently received four cycles of standard-dose etoposide-cisplatin.A total of 118 cycles of paclitaxel were administered with minimal hematological toxicity. Grade 2/3 peripheral neuropathy was observed in 21% of patients. Response rate to paclitaxel was 48.8%, and 25.6% had stable disease (SD). Thirty-two patients achieving SD or response to paclitaxel subsequently received a total of 90 topotecan cycles. Topotecan-related toxicities included febrile neutropenia in 15.6% of patients with one toxic death, grade 3/4 anemia in 25% of patients and grade 3/4 thrombocytopenia in 31.3%. Non-hematological toxicities were mild. At completion of sequential paclitaxel-topotecan treatment the overall response rate was 55.8% (22 partial response, two CRs). Median survival for all patients was 10.5 months and median progression-free survival was 8.5 months.Sequential treatment with dose-dense paclitaxel followed by topotecan is feasible despite significant hematological toxicity during topotecan treatment. This schedule is an active regimen in extensive-stage SCLC and merits further investigation.

Background : There is need for more active and better tolerated combinations in non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) therefore conducted this phase II study to define the efficacy and toxicity profile of the combination of higher doses than usual of gemcitabine along with cisplatin in patients with advanced NSCLC. Patients and methods : Forty patients with pathologically documented advanced NSCLC were included in this trial (34 men, six women; aged 34–74 years; mean 64 years). Twenty-two patients had unresectable stage IIIB disease and 18 had stage IV disease. Karnofsky performance status was ≥70%. In five patients, surgery had previously been performed and four patients had received radiotherapy. Gemcitabine at a dose of 1200 mg/m 2 was administered weekly (days 1, 8 and 15) and cisplatin 100 mg/m 2 on day 15 of each 28-day cycle. Results : Responses were scored according to standard World Health Organization criteria. Of 40 assessable patients, 19 had a partial response for an overall response rate of 47.5% (95% confidence interval (CI) 32–64%). To date, median survival for the whole group is 10.4 months (95% CI 6.2–11.7 months), with a 1-year survival rate of 35%. Toxicity was mainly haematological. Seven patients (18%) had grade 4 neutropenia (one episode of febrile neutropenia). Thrombocytopenia (12.8% grade 3 and 2.6% grade 4) was not associated with clinical bleeding. One patient had a grade 4 transient rise in transaminase. There was no grade 3 or 4 renal toxicity. There was no grade 4 symptomatic toxicity. The most common grade 3 toxicities were nausea and vomiting (28.2%) and alopecia (10.3%) both related to cisplatin. Conclusions : Gemcitabine can be safely administered at a dose of 1200 mg/m 2 in combination with cisplatin. Thrombocytopenia seems to be less than in schedules with cisplatin given on day 1. The results of this study show promising activity (47.5% response rate) with modest toxicity. As this combination of gemcitabine and cisplatin deserves further evaluation in prospective randomized trials, the SLCG is comparing gemcitabine–cisplatin with etoposide–cisplatin in a phase III randomized study.

Anorexia and cachexia are present in the majority of patients with advanced-stage cancer. Several agents have been tested for their ability to reverse weight loss in these patients. Megestrol acetate has been demonstrated to improve appetite and weight, independent of tumor response, when used in the treatment of metastatic breast cancer. Several trials have studied the ability of megestrol acetate to stimulate weight gain in patients with non-hormone-sensitive tumors. One hundred fifty patients with a weight lost of more than 5% in the 3 previous months were randomized between double-blind megestrol acetate 160 mg daily (LMA), megestrol acetate 480 mg daily (HMA), or placebo (P). Weight, mid-arm circumference, triceps skinfold thickness (TST), performance status (Karnofsky index), and a quality-of-life status by seven linear analogic self-assessment scales were assessed before the start of treatment and at 4, 8, and 12 weeks thereafter. One hundred seven patients were assessable at 4 weeks, 79 at 8 weeks, and 64 at 12 weeks. Sixty-eight percent of patients treated with HMA increased their weights during their permanence on study, versus 37% and 38% of patients treated with P or LMA (p < 0.03). The mean weight gain after 12 weeks of treatment with HMA was 5.41 kg. A significant increase on TST was observed in the HMA group versus the LMA and P groups. There was no gain in performance status or quality of life in any group of treatment. The toxicity registered was mild. There were no thromboembolic events. This trial supports the efficacy of megestrol acetate at 480 mg/day in the treatment of cancer-related cachexia and anorexia, with mild toxicity. However, performance status and quality of life were not influenced by this treatment.

1531 Background: Gender differences in lung cancer (LC) have been reported, but with many unresolved issues yet. Tobacco causes the majority of women lung cancer (WLC), although the rate of never-smoking WLC is higher than in men. Several factors may play etiologic roles, and an in-depth understanding is needed. Methods: WORLD07 is a Spanish prospective, multicenter, epidemiologic female-specific LC database sponsored by ICAPEM, a professional association committed with WLC research. In order to improve the knowledge on never-smoking WLC, information has been extracted from WORLD07 database. Results: From October/2007 to October/2011, 1371 newly diagnosed WLC were included in an e-database from 32 centers, 539 (39.3%) never-smoking. Patient (p) characteristics: median age 71.1 years(y); median age of menarche 13y.; motherhood 91.2% (median 2.3 children, median age at first child 26.4y); oral contraceptive use 11.9%; postmenopausal 88.9% (median age of menopause 49y); HRT 5.2%; second-hand smokers 40% (work-exposure 17.1%, home-exposure 88.8%); obesity 16.3%; familiar history of cancer 39.9% (LC 29.8%); previous history of cancer 13% (breast/lung/cervix: 41.4/5.7/2.9%); current LC histology(%): adenocarcinoma/SqCC/LCC/SCLC: 83.4/6.2/5.5/3.9; EGFR mut+ (268 p analyzed): 55.5% (exon 19/20/21(%): 61.1/7.4/36.9); TNM NSCLC I/II/III/IV(%): 14/3.3/19.8/60.3. Treatment: EGFR-TKI in p EGFR mut+, stage IV(1st-/2nd-line)(%): 51.7/15.4; stage IV NSCLC (1st-line/2nd-line): platinum-based CT 42.5%, EGFR-TKI 33.5%, combinations with bevacizumab 2.9% / EGFR-TKI 15.8%. Overall survival: median 27 months(m), 1/2-y(%) 74.8/55.2; stage IV NSCLC: median 20.5m, 1/2-y(%) 67/46; EGFR-mut+ p: median 27.3m, 1/2-y(%) 75/54.3. Conclusions: According to our e-database, WLC showed high rates of never-smokers (39.3%), and of relatives diagnosed with malignant tumours (39.9%, ≅1/3 LC). Adenocarcinoma was the most frequent histology (76.1%), and more than half of the cases analyzed harboured EGFR mutations. Although 40% were second-hand smokers, further investigations are warranted. Survival outcomes remain satisfactory, as expected from this selected subgroup of p. Additional epidemiologic and treatment data will be presented.

Despite the knowledge of strong prognostic factors such as stage and performance status, the outcome of individual patients with non-small cell lung cancer is not yet predictable, although it has been observed that patients whose tumors contain K-ras gene mutations at codon 12 have a shortened survival. We compared response rate, toxicity and survival of patients with non-small cell lung cancer receiving carboplatin 325 mg/m2 on day 1 with either intravenous etoposide (100 mg/m2 days 1-3) or oral etoposide (50 mg/m2/day) for 21 consecutive days. Secondly, we sought to find whether K-ras mutations or their genotypes could help to distinguish tumor types with clinical implications on prognosis. 180 patients were entered in this randomized study. Tumor specimens obtained at the time of bronchoscopy were available in 71 cases. 167 patients were assessable for response. We obtained 24 objective responses out of 88 patients (27%) in the intravenous etoposide plus carboplatin arm and 14 out of 79 patients (18%) in the oral etoposide plus carboplatin arm. Neither the objective response rate nor the survival time showed a significant difference between the two groups. Toxicity consisted mainly of myelosuppression. We detected 20 ras gene mutations in the 71 (28%) tumors analyzed. None of the 7 patients with aspartic and serine ras mutations had objective response as compared with 2 of 13 patients (15%) whose tumors contained cysteine, valine and arginine mutations and 16 of the 51 patients (31%) who had no ras mutations. Patients whose tumors had aspartic and serine mutations had a median survival time of 18 weeks in contrast with 36 weeks for the remainder (P=0.04). This study highlights the fact that K-ras genotypes may be an important prognostic variable in patients with advanced non-small cell lung cancer.

7322 Background: CCR in unresectable NSCLC has been superior to sequential approach in several studies. However, concurrence often precludes administration of full-dose chemotherapy. So, induction chemotherapy followed by CCR seems a promising alternative. A phase I study confirmed the feasibility of CCR with biweekly, low-dose, gemcitabine in NSCLC patients (Blackstock, ASTRO99). Methods: Inclusion criteria: unresectable stage III NSCLC, Karnofsky >70,adequate pulmonary, hematologic, renal and liver functions, and planned treated volume

PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

Purpose The present article reports the results of a multicentre phase II study analysing both activity and tolerance of the cisplatin vinorelbine combination in patients with inoperable NSCLC.

PURPOSE Anti-Hu antibodies (HuAb) recognize antigens expressed by neurons and small-cell lung cancer (SCLC). High titers of HuAb were initially reported in serum from patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) and SCLC. Preliminary studies have indicated that some SCLC patients without PEM/SN harbor low titer of HuAb in their serum, and that the SCLC of these patients may grow more indolently. Based on these observations, we conducted a multicenter prospective study of SCLC patients without PEM/SN to determine the incidence and prognostic implications of HuAb. METHODS Serum samples were collected at diagnosis of SCLC in 196 patients without PEM/SN. HuAb were determined by immunoblot of purified recombinant HuD antigen. RESULTS HuAb were detected in 32 (16%) of the 196 patients. Of the 170 patients who received treatment for the tumor, 27 (16%) were HuAb positive. HuAb was associated with limited disease stage (59.3% v 38.6%; P = .047), complete response to therapy (55.6% v 19.6%; P < .001), and longer survival (14.9 v 10.2 months; P = .018). In a logistic regression analysis, HuAb status was an independent predictor of complete response induction. The probability of achieving a complete response was more than five times higher in HuAb-positive than in HuAb-negative patients (odds ratio, 5.4; 95% confidence interval, 1.71 to 16.89; P = .004). Cox multivariate analysis indicated that HuAb status was not independently associated with survival. CONCLUSION The presence of HuAb at diagnosis of SCLC is a strong and independent predictor of complete response to treatment. This feature accounts for the association between HuAb and longer survival.

High-dose epirubicin plus cisplatin was compared with the reference regimen of etoposide/cisplatin in small-cell lung cancer (SCLC). Four hundred two previously untreated patients with SCLC were randomized to receive etoposide 100 mg/m(2) on days 1-3 and cisplatin 100 mg/m(2) on day 1 or epirubicin 100 mg/m(2) and cisplatin 100 mg/m(2) on day 1 every 21 days for a total of 6 cycles. Patients were stratified according to treatment center and extent of disease (limited disease, n = 207; extensive disease, n = 195). Patients with limited disease were treated with thoracic radiation therapy after completion of chemotherapy, and those who exhibited a complete response were advised to receive prophylactic cranial irradiation. The primary endpoint was survival, and secondary endpoints were time to progression (TTP), response, toxicity, and costs. Patient characteristics were generally well balanced in the 2 arms, even though more patients in the epirubicin/cisplatin arm had > 5% weight loss and poor Karnofsky performance index compared with the etoposide/cisplatin arm. One hundred thirty-four patients (66.3%) in the etoposide/cisplatin arm and 126 (63.0%) in the epirubicin/cisplatin arm received all 6 planned cycles of chemotherapy. Response rate, TTP, and survival did not differ significantly between the 2 arms. Grade 3/4 neutropenia and toxic deaths occurred more frequently in the etoposide/cisplatin arm. Epirubicin/cisplatin showed a similar activity with a slightly lower toxicity profile than the reference regimen of etoposide/cisplatin. The epirubicin/cisplatin regimen may be recommended in the treatment of SCLC.