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7514 Background: Lungscape allowed building the largest virtual biobank of radically resected NSCLC with comprehensive annotated clinical data, with the aims of expediting knowledge on biomarkers and facilitating translation of research to the clinic. Methods: 2,403 stage I-III radically resected NSCLC cases from 15 sites with mandatory comprehensive clinical annotations including at least 2 years of follow-up have been collected retrospectively. A systematic data review of every single case was performed. Relapse-free survival (RFS), time to relapse (TTR) and overall survival (OS) have been analyzed overall and by subgroups. Results: Median age of the cohort is 66 years, with 35% women, and respectively 14%, 32% and 49% never, current and former smokers. Histological types included 52% adenocarcinoma, 40% squamous cell carcinoma, and 4.5% large cell carcinoma and some rarer/mixed subtypes. As shown in the Table, median RFS, TTR and OS differ significantly by stage (p

High-dose chemotherapy with autologous bone marrow transplantation is used in the treatment of relapsed or high-risk Hodgkin's disease. As prospective randomised studies have proved difficult to accrue to, current recommendations are based on the reports of large series of prospectively collected data. We have looked at the outcome of 89 patients treated in this way at a single institution and have developed an index to predict outcome. Of 89 patients, with a median age of 29 years (range 15-51 years), eight patients were in first complete remission/partial remission (CR/PR), 17 in second or later CR, 37 were responding relapses, 13 resistant relapses, 11 primary refractory and three untested relapses. Combinations of melphalan, BCNU and etoposide were given in all cases except in ten patients who received melphalan alone. The median follow-up was 43 months (range 6-77 months). A total of 24 patients were in CR at the time of autologous bone marrow transplantation (ABMT), 33 achieved CR with ABMT, 16 PR, to give a response rate to ABMT of 49/65 = 74% (95% CI 60-83%) with a CR rate of 51% (CI 36-62%). In a Cox's multivariate analysis the most important factors in predicting outcome after ABMT were response to treatment before entry, number of previous treatments and previous chemosensitivity. Using these factors we devised a prognostic index which reliably selects a group of patients (65%) with at least a 70% chance of being progression free from 1 year onwards. Patients who have never achieved a CR and have received three or more chemotherapy regimens do not benefit from high-dose chemotherapy as used in this study.

A pilot study of continuous infusional 5-fluorouracil 200 mg m-2 per 24 h by ambulatory pump and Hickman line for the entire treatment cycle with mitomycin C 8 mg m-2 i.v. on day 1 and cisplatin 75 mg m-2 i.v. on day 1, both repeated every 28 days, was carried out in 31 previously untreated patients with advanced non-small-cell lung cancer (NSCLC). Of 31 patients assessable for response, one attained a complete remission and eight a partial remission, an overall response rate of 29%. Haematological toxicity was minimal, with only 3% of patients developing WHO grade III/IV neutropenia and 13% grade III/IV thrombocytopenia. Significant side-effects included moderate to severe emesis (41%), mucositis (34%), diarrhoea (31%) and palmar-plantar syndrome (14%). Seven patients (23%) had Hickman line complications requiring line removal. Continuous infusional chemotherapy with this regimen is active in advanced non-small-cell lung cancer, but its complexity and associated treatment toxicity offer little advantage over equally active but simpler and less toxic cisplatin-based regimens.

A 32-year-old Caucasian man presented with a 2-month history of fatigue, 4 kg weight loss and vague dyspepsia. He described no vomiting and no lower gastrointestinal symptoms. He was previously healthy with no significant past medical history, did not smoke and consumed around 10 units of alcohol per week. Systemic examination was normal. Blood tests revealed a mild normocytic anaemia (haemoglobin 128 g/l) with normal haematinics. Urea and electrolytes, liver function tests, calcium and c reactive protein were all within normal limits. Upper gastrointestinal endoscopy revealed an unusual raised lesion in the second …

Background The Lungscape project aims at building a virtual biobank to facilitate an international high-quality analysis of large numbers of tumors for molecular alterations linked to clinical and biological characteristics captured in the iBiobank. Methods Retrospective radically resected stage I-III non-small cell lung cancer cases from 15 ETOP centers, with mandatory comprehensive clinical annotations including at least 2 years of FU have been reviewed and captured. Results This first set of 1614 cases was enriched in adenocarcinoma (61.8%), with 28.8% of squamous and 4.9% of large cell histologies. Median age is 65 yrs, 37.6% are women, and respectively 13.9%, 33.5% and 49.6% are never, current and former smokers. Stage distribution is: IA 23.7%, IB 25.8%, IIA 16.4%, IIB 11.6%, IIIA 20.8%, IIIB 1.7%. At last FU, 52.8% of patients were still alive, with a median FU of 5.3 yrs. PFS No. of patients 5 years (95% C.I.) Median (mos) (95% C.I.) TOTAL 1614 46 (43.3, 48.6) 49.0 ( 43.9, 55.2) Stage Ia 382 64.5 (59.1, 60.5) NR Ib 417 55.4 (50.3, 60.5) 78.0 IIa 264 44.8 (38.4, 51.3) 46.9 IIb 187 39.2 (31.6, 46.8) 33.7 IIIa 335 20.0 (15.2, 24.8) 17.5 IIIb 28 11.9 (0.0, 25.3) 10.1 OS 1614 52.0 (49.3, 54.7) 64.2 (57.3, 76.9) Stage Ia 382 70.0 (64.9, 75.2) NR Ib 417 60.6 (55.5, 65.7) NR IIa 264 50.5 (43.8, 57.1) 62.2 IIb 187 43.7 (36.0, 51.4) 43.3 IIIa 335 29.3 (23.9, 34.7) 29.0 IIIb 28 10.3 (0.0, 27.1) 20.2 Conclusion This is the first large-scale series based on 7th TNM classification reporting on OS and PFS in the context of European standards of care. These data confirm the discriminative capacity of the 7th TNM with a potentially somewhat superior outcome. Histologies other than adenocarcinoma are currently actively being captured. Complete data including PFS and TTP - never reported before - as well as OS based on the expected 2400 patients correlated to stage, gender, smoking status, histology and age will be provided. This complete clinical dataset will be invaluable to investigate the impact of molecular characteristics on outcome. It will allow building future hypothesis for prospective evaluation of new treatment strategies and help in the development of a molecularly refined TNM. Disclosure All authors have declared no conflicts of interest.

7583 Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p

Background The standard of care for advanced NSCLC is platinum-based chemotherapy but the optimal dose of cisplatin and comparison with carboplatin is uncertain. With median survival at 8–12 months, the impact of such treatment choices on patients9 quality of life (QoL) is important. The BTOG2 trial is a large phase III randomised trial comparing three treatment arms: gemcitabine (1250 mg/m 2 day 1 and day 8) with either cisplatin 80 mg/m 2 (GC80), cisplatin 50 mg/m 2 (GC50) or carboplatin AUC6 (GCb6). The trial was innovative in aiming to collect QoL data on all trial patients and is the largest study to date addressing this issue in NSCLC. Methods QoL was measured at each cycle of chemotherapy and each follow-up visit using standard, validated questionnaires: EORTC QLQ-C30, LC13 and EQ-5D. Results More than 8000 questionnaires were returned from 1363 randomised patients with compliance around 90% during the treatment period. At pre-randomisation, the mean global heath status score and EQ-5D utility score were 62% and 0.66. On initiation of treatment, patients in all three treatment arms had improved pain, cough, haemoptysis, insomnia, appetite loss and emotional functioning with associated improvements in global measures of QoL but these benefits generally fell away after completion of chemotherapy (12+ weeks). GC50 performed better in terms of the functioning scores and in terms of fatigue, nausea and vomiting while GCb6 performed worst for dyspnoea. All treatments had a deleterious effect on peripheral neuropathy with the post-treatment toxicity momentum markedly worse for GC80. Mean quality-adjusted life months were 6.1 on GC80, 5.6 on GC50 and 6.1 on GCb6. Conclusion Although higher doses of cisplatin (80 mg/m 2 ) are thought detrimental to QoL compared to 50 mg/m 2 we found minimal differences but a noteworthy problem in delayed neuropathy. Also, the belief that carboplatin produces superior QoL compared to cisplatin at either dose is not obvious. Importantly carboplatin treatment may not palliate dysponea as well as cisplatin. Adjusting for QoL does not change the conclusions from the primary survival analysis.

Background Platins are considered key drugs in treating advanced NSCLC. Carboplatin has been reported as inferior to cisplatin in meta-analyses while the optimal dose of cisplatin is unclear. Methods Eligibility was by histologically proven NSCLC, PS 0–2, stage IIIB/IV disease and a GFR of >60 ml/min, using the Wright equation. Treatment was gemcitabine (1250 mg/m 2 ) combined with cisplatin 50 mg/m 2 , cisplatin 80 mg/m 2 or carboplatin AUC 6, for up to four cycles. Carboplatin dosing was calculated using the Calvert equation. At the time of analysis 1223 deaths had been reported, allowing analysis according to the statistical plan. Results 1363 patients were randomised between April 2005 and November 2009. Trial arms were well balanced for PS, stage and age. Median age was 63, 32% were PS0, 60% PS1 and 8% PS2. The median delivered dose intensities (planned=100%) for platinum were GC50 99%, GC80 96% and GCb6 87%, for gemcitabine were 95%, 88% and 80% respectively. During treatment the proportion of patients experiencing at least one grade 3/4 AE were; GC50 27%, GC80 41% and GCb6 57%. At analysis 140 patients were alive and median follow-up was 21 months. Response rates were significantly different between arms; GC50 23%, GC80 33% and GCb6 28% (p=0.01). Median survival was: GC50 8.3 months, GC80 9.5 months and GCb6 10.0 months, with the GC50 arm statistically identified as differing from the other two. For subsequent primary comparisons of non-inferiority of GC50 v GC80 (HR=1.11) and GCb6 v GC80 (HR=0.96), the 95% CI for the cisplatin dose comparison (0.96, 1.27) did not exclude the pre-defined inferiority region of HR>1.2 whereas the 95% CI for the GCb6 v GC80 comparison (0.84, 1.10) fell well below this inferiority region. Conclusion In advanced NSCLC the dose of cisplatin is important with GC50 giving the poorest outcome in terms of overall survival and response rate. GCb6 is not inferior to GC80 thus, in combination with gemcitabine, and in relation to survival time, carboplatin is clinically equivalent to that of cisplatin but other factors, such as quality of life, may influence treatment choice.

e21065 Background: Carcinomas of unknown primary origin (CUP) constitute 3-10% of all cancers, and rank in the top ten commonest malignancies. The prognosis is poor, with a median survival of 8-12 ...

Three hundred patients with symptomatic, locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this randomized multicentre trial comparing gemcitabine + BSC vs BSC alone. Patients allocated gemcitabine received 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, for a maximum of six cycles. The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms (SS14) from the EORTC QLQ-C30 and LC13 scales. The primary end-points were defined as (1) the percentage change in mean SS14 score between baseline and 2 months and (2) the proportion of patients with a marked (or = 25%) improvement in SS14 score between baseline and 2 months sustained foror =4 weeks. The secondary objectives were to compare treatments with respect to overall survival, and multidimensional QL parameters. The treatment groups were balanced with regard to age, gender, Karnofsky performance status (KPS) and disease stage (40% had metastatic disease). The percentage change in mean SS14 score from baseline to 2 months was a 10% decrease (i.e. improvement) for gemcitabine plus BSC and a 1% increase (i.e. deterioration) for BSC alone (P = 0.113, two-sample t-test). A sustained (or = 4 weeks) improvement (or =25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearson's chi-squared test). The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm (in 11 domains) than in the BSC arm (one symptom item). There was greater deterioration in the BSC alone arm (six domains/items) than in the gemcitabine + BSC arm (three QL domains). Tumour response occurred in 19% (95% CI 13-27) of gemcitabine patients. There was no difference in overall survival: median 5.7 months (95% CI 4.6-7.6) for gemcitabine + BSC patients and 5.9 months (95% CI 5.0-7.9) (log-rank, P = 0.84) for BSC patients, and 1 -year survival was 25% for gemcitabine + BSC and 22% for BSC. Overall, 74 (49%) gemcitabine + BSC patients and 119 (79%) BSC patients received palliative radiotherapy. The median time to radiotherapy was 29 weeks for gemcitabine + BSC patients and 3.8 weeks for BSC. Patients treated with gemcitabine + BSC reported better QL and reduced disease-related symptoms compared with those receiving BSC alone. These improvements in patient-assessed QL were significant in magnitude and were sustained.

e18120 Background: Improved clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in non-small cell cancer (NSCLC) patients (pts) with sensitizing mutations (mu) of the EGFR, along with Euro...

TPS293 Background: Nonsquamous (NS-) NSCLC is a predictive factor for response to pemetrexed (pem). Laboratory evidence suggests that this differential outcome may be related to low TS mRNA expression in NS-NSCLC. In this exploratory phase II trial the primary objective ( PO) is to test prospectively, the correlation between TS protein expression (TSPE) and progression free survival (PFS). This abstract reports the TS assay (TSA) protocol to measure TSPE using IHC. Methods: An open-label, single-arm, multicentric study (with appropriate UK approvals) was undertaken to test the PO in eligible patients (n=68) receiving pem/cisplatin induction followed by maintenance pem until tumour progression (PD). Key eligibility criteria included ECOG PS 0-1, histological diagnosis of stage IIIB/IV NS-NSCLC, and informed consent. The TSA protocol for this study was designed on a validated procedure developed by study sponsors. Diagnostic slides and FFPE blocks are centrally collected for diagnostic verification and TS s...

e12056 Background: Treatment and survival rates within Scotland for patients with lung cancer appear lower than in many other European countries with the 5-year survival being quoted as 5-6% compared with 8%-15% in other European countries and the United States no study of lung cancer has attempted to specifically investigate the association between variation in investigation, comorbidity and treatment and outcome between different centres. Methods: Patient demographics (gender, age, postcode, smoking history), WHO/ECOG performance status (at presentation and estimated 6 months prior) and primary treatment modality were recorded. If a histological diagnosis was not achieved, this, along with the reason(s) why not, was recorded (age, poor performance status, comorbidity, nondiagnostic investigations, patient choice) along with the investigations attempted, clinical/radiologic stage and primary treatment plan. In addition to recording the comorbidities present in each patient, the severity of each comorbidi...

9020 Aim: To evaluate QL during the first 2 years follow-up in patients randomised to receive 3 cycles of platinum-based chemotherapy (CT-S) prior to surgical resection of NSCLC compared to those receiving surgery alone (S). Methods: A total of 519 patients were entered into the LU22 trial from 70 centres in the UK, The Netherlands, Germany and Belgium. All patients were asked to complete the SF-36 QL questionnaire prior to randomisation and at 6 and 12 months then annually to 5 years. The scores from the SF-36 questionnaire were combined into 8 domains and also summarised as physical component summary (PCS) and mental component summary (MCS). The 6,12 and 24 month PCS and MCS scores were analysed using multivariable regression to identify prognostic factors and investigate the difference between the regimens. Results: 82% patients completed QL at baseline, and compliance at 6, 12 and 24 months was 59%, 60% and 67% respectively. Median age was 63 (range 25 to 79 years) and 72% were male. At 6 months patients in the S group reported somewhat better functioning in all domains except general health and mental health, but no differences were seen at 12 or 24 months. The regression analyses indicated that better physical health outcomes (PCS) were predicted by baseline PCS and MCS at all follow-up points (all p [Table: see text]

3597 Background: The survival benefit associated with erlotinib is greater in never smokers than in current smokers. Former/never smokers experience a higher incidence of toxicity (e.g., rash) than current smokers, potentially due to greater erlotinib exposure. A higher dose of erlotinib, if feasible, may improve outcome in current smokers. Methods: A 2-part study was initiated to investigate the feasibility of escalating erlotinib to define the MTD in smokers and evaluate pharmacokinetics in patients (pts) dosed at this MTD versus 150 mg/d. Part I: sequential cohorts of advanced NSCLC pts currently smoking =10 cigarettes/d for = 1yr, ECOG PS 0–1, adequate organ function, and no prior EGFR inhibitor, received escalating doses of erlotinib for 14 days until DLT was seen in 2/6 pts. Part II: Upon identification of the MTD, pts were randomized between MTD and 150 mg/d erlotinib and PK assessed at D14. Pts could receive erlotinib beyond D14 until PD or toxicity. Results: Twenty-two pts were enrolled in Part I at 4 dose levels (#pts (MTD-evaluable pts)/dose level in mg/d): 3(3)/200, 6(3)/250, 8(6)/300 and 5(5)/350). Median/range age was 61 yrs (45–69) with 13 males and 9 females. Histology was Adenocarcinoma (9/22), Squamous (6/22) and other (7/22). Fourteen pts had prior RT and all had prior CT (median/range # prior regimens 1 (1–2)). Median/range # cigarettes smoked and duration of smoking was 18/d (10–40) and 42 yrs (10–54), respectively. DLT was observed in 1/6 MTD- evaluable pts at 300 mg/d (G3 rash) and 2/5 pts at 350 mg/d (G3 acneiform dermatitis and G3 fatigue/decreased ECOG PS). Otherwise treatment was well tolerated with common G1/2 toxicities limited to skin toxicity (59%), diarrhea (55%), and nausea, vomiting and metabolic or eye disorders (each 14%). Conclusions: The MTD of erlotinib in NSCLC pts who continue to smoke was 300 mg/d. Part II continues to compare the steady state PK of erlotinib at 300 versus 150 mg/d. The potential benefits of a higher dose of erlotinib in current smokers may warrant further evaluation. No significant financial relationships to disclose.

7518 Aims: Although surgery offers the best chance of cure for patients with NSCLC, the overall 5-year survival rate is modest, and improvements are urgently required. This intergroup trial was designed to investigate whether, in patients with operable NSCLC of any stage, neo-adjuvant platinum-based chemotherapy prior to surgery would improve outcomes. Methods: Patients were randomised to receive either surgery alone (S), or 3 cycles of platinum-based chemotherapy prior to surgery (CT-S). Results: 519 patients were randomised (261 S, 258 CT-S) from 70 centres in the UK, the Netherlands, Germany and Belgium. The median age of the patients was 63 years, 72% were male, 59% were PS 0, and 50% had squamous cell histology. The majority were clinical stage I (17% Ia, 45% Ib, 3% IIa, 29% IIb, 7% IIIa), and 12% received mitomycin/vinblastine/cisplatin (MVP), 7% mitomycin/ifosfamide/cisplatin (MIC), 45% vinorelbine/cisplatin, 12% carboplatin/docetaxel, and 25% cisplatin/gemcitabine. The trial showed that neo-adjuvant chemotherapy was feasible (76% of patients received all 3 cycles of chemotherapy), resulted in a good response rate (4% CR, 45% PR, and only 2% PD), appeared to cause down-staging in about 20% of patients, and did not affect the type of surgery performed, the post-operative complication rate, or quality of life. However, there was no evidence of a benefit in terms of progression-free survival (282 events, HR 0.98, 95% CI 0.77,1.23) or overall survival (232 deaths, HR 1.04, 95% CI 0.81, 1.35), and more patients were reported as having brain metastases in the CT-S group (30 CT-S vs 11 S patients). Exploratory analyses showed no evidence that any subgroup of patients benefited from the addition of neo-adjuvant chemotherapy. Conclusions: This intergroup trial, which is the largest trial of neo-adjuvant chemotherapy in patients with resectable NSCLC, indicated that the addition of neo-adjuvant platinum-based chemotherapy did not lead to a benefit in overall survival. However, a 19% survival benefit or a 35% detriment cannot be excluded and this result needs to be considered in the context of all other relevant randomised trials of neo-adjuvant chemotherapy for NSCLC. [Table: see text]

15001 Background: In advanced OG cancer, it is unclear whether squamous cell carcinoma (SCC) differs from adenocarcinoma (Ad) in its response to chemotherapy, as most phase III studies do not include both histology. The aim of this pooled analysis was to evaluate whether there is a differential chemotherapy effect on overall survival (OS), response rate (RR) and toxicity depending on tumour histology (SCC vs. Ad) using individual patient (pt) data. Methods: From 1994 to 2005, 3 RCTs were conducted assessing fluoropyrimidine ± platinum-based chemotherapy. This analysis was restricted to eligible pts with SCC or Ad histology who received =1 dose chemotherapy. Apart from OS and RR, a toxicity composite endpoint (TCE) was constructed - defined as occurrence of grades =3 diarrhoea, (febrile) neutropenia, infection, nausea & vomiting, grades =2 renal and neurotoxicity. Ad was used as the control group. Two-sided p values of No significant financial relationships to disclose.

LBA4017 Background: The aim was to establish the potential use of the third generation platinum compound, oxaliplatin (O) & the oral fluoropyrimidine capecitabine (X) in untreated patients (pts) with advanced OG cancer. Methods: After stratification for PS and extent of disease, pts with histologically confirmed adenocarcinoma, squamous or undifferentiated carcinoma of the oesophagus, oesophago-gastric junction or stomach were randomised, in a 2 x 2 design, to 1 of 4 regimens; epirubicin, cisplatin, fluorouracil (ECF), EOF, ECX or EOX. Doses E 50 mg/m2, C 60 mg/m2 & O 130 mg/m2 IV 3 weekly; F 200 mg/m2 IV daily & X 625 mg/m2 twice daily PO continuously; for 8 cycles. The primary endpoint was overall survival. With 1000 pts (250 per arm) the study had 80% power to demonstrate non-inferiority of X over F and also O over C if the upper limit of the HR 95% CI excluded 1.23 (α = 0.05) in the per protocol population. Analysis was performed using the logrank test and Cox regression analysis. Results: 1002 pts were randomised from 61 centres. Demographics were balanced, 89% were PS 0–1, 77% metastatic, median age 63 (range 22–83), 81% were male and 40% gastric primaries. Histology: adenocarcinoma in 88% and 52% poorly differentiated. 11 pts were ineligible and 27 pts were withdrawn before treatment commenced. Median follow up was 17.1 months and 850 events have occurred. There were no significant differences in response rates comparing ECF to, EOF, ECX and EOX (41%, 42%, 46%, and 48% respectively); grade 3–4 non haematological toxicity 36%, 42%, 33% and 45%; and grade 3–4 neutropaenia 42%, 30% (p = 0.008), 51% (p = 0.043) and 28% (p = 0.001) respectively. Conclusions: Capecitabine may replace 5FU and Oxaliplatin may replace Cisplatin in triplet regimens used for the treatment of advanced OG cancer. [Table: see text] [Table: see text]

7066 Background: Phase III studies suggest higher response rates and better survival in patients with NSCLC treated with a combination of cisplatin and docetaxel (DC) compared to older cisplatin based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC/MVP in patients with advanced NSCLC. Methods: 432 patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy and PS 0–2 were randomised to receive either 4 cycles of DC (docetaxel 75mg/m2, carboplatin AUC 6) or 4 cycles of either MIC (mitomycin 6mg/m2, ifosfamide 3gm/m2, cisplatin 50 mg/m2) or MVP (mitomycin 6mg/m2, vinblastine 6mg/m2, cisplatin 50mg/m2), 3 weekly. The primary end-point was 1-year survival, secondary endpoints were response rates, toxicity and QOL (EORTC QLQ-C30, HADS and LC13). Results: 419 patients were eligible and 87 (21%) were of PS2. There were less stage IV (48 v 54%, p=0.26) and PS2 patients (18 v 23%, p=0.28) in the DC arm. The radiologi...

2104 Background: Improved understanding of the molecular mechanisms underlying NSCLC pathogenesis and how these can be exploited by systemic therapies will lead to improved clinical outcomes. Using global gene expression profiling, we have previously shown that caspase independent programmed cell death pathways may be critical in mediating response to platinum based therapy in NSCLC. Methods: Tumour: uninvolved adjacent paired tissues from NSCLC patients who received platinum based neoadjuvant chemotherapy have been profiled (Affymetrix HG-U133A GeneChips). Gene expression data was validated using quantitative RT-PCR and data was analysed using Affymetrix MASv5.0, MicroDBv3.0, DMTv3.0 and GeneSpringv6. Results: In a supervised data analysis, inhibition of caspase dependent cell death is a universal finding in NSCLC which bears no correlation to response to therapy. In contrast, pathways of caspase independent cell death are blocked in non-responders but appear functional in responders. In non-responding t...

Sixty-five patients with locally advanced or metastatic pancreatic cancer were treated with Cisplatin (60 mg/m 2 3 weekly) and protracted venous infusion 5-fluorouracil (PVI 5FU 300 mg/m 2 /day) for a maximum of 24 weeks. All patients had histologically/cytologically confirmed tumour. Radiological response was assessed by CT scanning and toxicity, performance status and symptomatic response was assessed 3 weekly. The objective response rate was 16% (9/57) with two radiological complete responses. Disease stabilisation was seen in 82% patients (47/57) with 8 patients non-evaluable for response. The median survival was 7.6 months with 1 year survival of 33% and a median progression free survival of 6.6 months. Patients who had local disease only had a median survival of 14.6 months with a 1 year survival of 53%. Thirty-four percent of patients (20/59) had an improvement in performance status on treatment and specific symptoms which improved were weight loss (30/39; 77%), dysphagia (4/4; 100%), nausea and vomiting (29/39; 74%), pain (27/39; 69%), anorexia (18/33; 55%) and reflux (18/22; 82%). Chemotherapy was well tolerated with grade 3 or 4 toxicity being nause/vomiting in 4%, diarrhea in 6%, infection 3%, stomatitis 1% and plantar palmar syndrome 1%. Grade 3 neutropenia occurred in 3% of patients with grade 3 thrombocytopenia in 4%. In conclusion, the CF regimen provides good symptomatic palliation with low toxicity in patients with pancreatic cancer.

Introduction: In a previous biomarker discovery project using gene-expression profiling we identified Serpin B3 (SB3) as a predictor of resistance to platinum doublet chemotherapy (PtC) in non–small-cell lung cancer (NSCLC). This independent prospective study was designed to confirm the predictive utility of SB3. Methods: SB3 immunohistochemistry was scored by previously validated criteria (score 0=negative, score 1=1%–10% tumor cells positive, score 2=11%–50% tumor cells positive, and score 3=>50% tumor cell positive) in 197 patients with stage IV NSCLC treated with PtC. This provided 80% power to detect a median survival increase from 150 days in patients with an SB3 immunohistochemistry score of 2 or more to 300 days in those with an SB3 score of 0 or 1. Results: Thirty-six percent of NSCLCs stained positive for SB3. Median survival for SB3 negative/score 0 was 332 days, SB3 positive/score 1 was 268 days, and SB3 positive/score 2 or 3 was 120 days ( p = 0.004). Cox proportional hazards analysis demonstrated that SB3 positivity is an independent predictor of survival (hazard ratio=1.87; 95% confidence interval, 1.29–2.71; p = 0.001).The disease control rate in SB3 score 0, 1=65%, and score of 2 or more=20 % ( p = 0.002), with median survival 306 days (score 0, 1) versus 120 days (score ≥2, hazard ratio=1.71; 95% confidence interval. 1.14–3.10; p = 0.002). Conclusions: SB3-positive immunohistochemistry score of 2 or more (>10% tumor cells positive) identifies a subgroup of patients with stage IV NSCLC who have a poor survival (median 120 days) when treated with PtC, similar to that estimated for untreated or chemo-refractory stage IV NSCLC. Further prospective qualification using biospecimens from randomized studies is needed, but SB3 seems to be a useful biomarker that identifies a highly resistant subgroup in whom PtC should be avoided.

Background: Treatment and survival rates within Scotland for patients with lung cancer seem lower than in many other European countries. No study of lung cancer has attempted to specifically investigate the association between variation in investigation, comorbidity, and treatment and outcome between different centers. Methods: Patient demographics, World Health Organization/Eastern Cooperative Oncology Group performance status, and primary treatment modality were recorded. In addition to recording the comorbidities present in each patient, the severity of each comorbidity was graded on a 4-point scale (0–3) using validated severity scales. Data were collected as the patient was investigated and entered in an anonymized format into a database designed for the study. Results: Prospectively collected data from 882 patients diagnosed with lung cancer in four Scottish centers. A number of statistically significant differences were identified between centers. These included investigation, treatment between centers (i.e., surgical rates), age, tumor histology, smoking history, socioeconomic profile, ventilatory function, and performance status. Predictors of declining performance status included increasing severity of a number of comorbidities, age, lower socioeconomic status, and specific centers. Conclusions: This study has identified many significant intercenter differences within Scotland. We believe this to be the first study to identify nontumor factors independent of performance status that together limit the ability to deliver radical, possibly curative, therapy to our lung cancer population. It is only by identifying such factors that we can hope to improve on the relatively poor outlook for the majority of Scottish patients with lung cancer.

PURPOSE To present long-term follow-up data of patients with myeloma treated with high-dose melphalan HDM, including an assessment of prognostic factors. PATIENTS AND METHODS Between November 1981 and April 1986, 63 previously untreated patients with multiple myeloma received HDM 140 mg/m2 without autologous bone marrow transplantation. RESULTS The overall response rate was 82% (51 of 62), with 32% (20 of 62) patients entering complete remission (CR). The median duration of response was 18 months, and six patients remain alive and free from disease progression at 60+ to 84+ months. Improvements in quality of life associated with remission were immediate in terms of pain grade (89% of patients) and performance status (92%), and later in terms of bone healing (29%). Currently, at a median follow-up duration of 74 months (range, 63 to 100) since HDM, 23 patients are alive with a median survival duration of 47 months, and 35% of patients are expected to be alive at 9 years. Apart from early-stage disease, no factors were found to predict long-term survival. No second malignancies or other late side effects have been recorded. CONCLUSION Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is associated with a high objective response rate, relatively long remission durations, and good symptom control.

The purpose of this study was to determine the effect of the first rat monoclonal antibody (MAb ICR62) to the epidermal growth factor receptor (EGFR) in a phase I clinical trial in patients with unresectable squamous cell carcinomas. This antibody effectively blocks the binding of EGF, transforming growth factor (TGF)-alpha and HB-EGF to the EGFR, inhibits the growth in vitro of tumour cell lines which overexpress the EGFR and eradicates such tumours when grown as xenografts in athymic mice. Eleven patients with squamous cell carcinoma of the head and neck and nine patients with squamous cell carcinoma of the lung, whose tumours expressed EGFR, were recruited. Groups of three patients were treated with 2.5 mg, 10 mg, 20 mg or 40 mg of ICR62 and a further eight patients received 100 mg. All patients were evaluated for toxicity using WHO criteria. Patients' sera were tested for the clearance of MAb ICR62 and the development of human anti-rat antibodies (HARA). No serious (WHO Grade III-IV) toxicity was observed in patients treated with up to 100 mg of antibody ICR62. Antibody ICR62 could be detected at 4 h and 24 h in the sera of patients treated with 40 mg or 100 mg of ICR62. Only 4/20 patients showed HARA responses (one at 20 mg, one at 40 mg and two at 100 mg doses) and of these only the former two were anti-idiotypic responses. In four patients receiving doses of ICR62 at 40 mg or greater, biopsies were obtained from metastatic lesions 24 h later and examined for the localisation of ICR62 using anti-rat antibody reagent. In these patients we showed the localisation of MAb ICR62 to the membranes of tumour cells; this appeared to be more prominent at the higher dose of 100 mg. On the basis of these data we conclude that MAb ICR62 can be administered safely to patients with squamous cell carcinomas and that it can localise efficiently to metastases even at relatively low doses. Images Figure 2 Figure 3

PURPOSE Phase II studies have shown that the combination of interferon alfa-2b (IFN) and fluorouracil (5-FU) is active in patients with metastatic colon cancer. This study was designed to investigate whether treatment with the combination of IFN and 5-FU could improve the response rate, duration of response, or survival compared with treatment with 5-FU alone. PATIENTS AND METHODS Patients with histologically confirmed advanced colorectal cancer were randomized to receive 5-FU 750 mg/m2/d by continuous infusion for 5 consecutive days followed by weekly bolus 5-FU 750 mg/m2 either with or without IFN 10 MU subcutaneously three times weekly. Treatment was continued until disease progression or unacceptable toxicity for up to 12 months. RESULTS Radiologic response was observed in 26 of 106 assessable patients (25%): 10 of 52 (19%) in the group that received 5-FU plus IFN (all partial responses [PRs]) and 16 of 54 (30%) in the 5-FU-alone group (three complete responses [CRs] and 13 PRs) (P = .21). There was similarly no significant difference between the two groups in progression-free survival (median, 3 months), 1-year survival, or overall survival (median, 8 months). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .013), lymphopenia (P = .01), depression (P = .014), and alopecia (P = .002), and were significantly more likely to be withdrawn due to adverse events (P = .003). There were four toxic deaths, all of which occurred in patients who had received IFN. CONCLUSION At the doses and schedules used in this study, IFN affords no benefit to 5-FU in terms of response and survival and significantly increases toxicity for patients with advanced colorectal cancer.

PURPOSE We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer. PATIENTS AND METHODS Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL). RESULTS The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained. CONCLUSION The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.