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Supervivència lliure de progressió; Tumors neuroendocrins Supervivencia libre de progresión; Tumores neuroendocrinos Progression-free survival; Neuroendocrine tumors Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1–2, Ki-67 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis. The CLARINET study was sponsored by Ipsen, the manufacturer of lanreotide autogel/depot. Medical writing services were provided by Nicky French PhD of Watermeadow Medical (Macclesfield, UK) – an Ashfield Company, part of UDG Healthcare plc – sponsored by Ipsen Ltd, Slough, UK in accordance with Good Publication Practice guidelines.

Background Nab-paclitaxel plus gemcitabine (nabP+gemcitabine) offers modest survival gains for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Sequential scheduling of nabP+gemcitabine in a PDAC mouse model improved efficacy; this hypothesis was tested in a clinical trial. Methods Patients with previously untreated metastatic PDAC were randomised to receive nabP+gemcitabine administered either concomitantly on the same day, or sequentially, with gemcitabine administered 24 h after nabP. The primary outcome measure was progression-free survival (PFS). Secondary outcome measures were objective response rate (ORR), overall survival (OS), safety, quality of life (QoL) and predictive biomarkers. Results In total, 71 patients received sequential (SEQ) and 75 concomitant (CON) treatment. Six-month PFS was 46% with SEQ and 32% with CON scheduling. Median PFS (5.6 versus 4.0 months, hazard ratio [HR] 0.67, 95% confidence interval [95% CI] 0.47–0.95, p = 0.022) and ORR (52% versus 31%, p = 0.023) favoured the SEQ arm; median OS was 10.2 versus 8.2 months (HR 0.93, 95% CI 0.65–1.33, p = 0.70). CTCAE Grade ≥3 neutropaenia incidence doubled with SEQ therapy but was not detrimental to QoL. Strongly positive tumour epithelial cytidine deaminase (CDA) expression favoured benefit from SEQ therapy (PFS HR 0.31, 95% CI 0.13–0.70). Conclusions SEQ delivery of nabP+gemcitabine improved PFS and ORR, with manageable toxicity, but did not significantly improve OS. Clinical trial registration ISRCTN71070888; ClinialTrials.gov (NCT03529175).

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m 2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.FUNDING: Cancer Research UK and Roche.

BACKGROUND: Transarterial chemoembolisation (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma, while the multikinase inhibitor sorafenib improves survival in patients with advanced disease. We aimed to determine whether TACE with sorafenib improves progression-free survival versus TACE with placebo.METHODS: We did a multicentre, randomised, placebo-controlled, phase 3 trial (TACE 2) in 20 hospitals in the UK for patients with unresectable, liver-confined hepatocellular carcinoma. Patients were eligible if they were at least aged 18 years, had Eastern Cooperative Oncology Group performance status of 1 or less, and had Child-Pugh A liver disease. Patients were randomised 1:1 by computerised minimisation algorithm to continuous oral sorafenib (400 mg twice-daily) or matching placebo combined with TACE using drug-eluting beads (DEB-TACE), which was given via the hepatic artery 2-5 weeks after randomisation and according to radiological response and patient tolerance thereafter. Patients were stratified according to randomising centre and serum α-fetoprotein concentration (FINDINGS: Between Nov 4, 2010, and Dec 7, 2015, the trial enrolled 399 patients and was terminated after a planned interim futility analysis. 86 patients failed screening and 313 remaining patients were randomly assigned: 157 to sorafenib and 156 to placebo. The median daily dose was 660 mg (IQR 389·2-800·0) sorafenib versus 800 mg (758·2-800·0) placebo, and median duration of therapy was 120·0 days (IQR 43·0-266·0) for sorafenib versus 162·0 days (70·0-323·5) for placebo. There was no evidence of difference in progression-free survival between the sorafenib group and the placebo group (hazard ratio [HR] 0·99 [95% CI 0·77-1·27], p=0·94); median progression-free survival was 238·0 days (95% CI 221·0-281·0) in the sorafenib group and 235·0 days (209·0-322·0) in the placebo group. The most common grade 3-4 adverse events were fatigue (29 [18%] of 157 patients in the sorafenib group vs 21 [13%] of 156 patients in the placebo group), abdominal pain (20 [13%] vs 12 [8%]), diarrhoea (16 [10%] vs four [3%]), gastrointestinal disorders (18 [11%] vs 12 [8%]), and hand-foot skin reaction (12 [8%] and none). At least one serious adverse event was reported in 65 (41%) of 157 patients in the sorafenib group and 50 (32%) of 156 in the placebo group, and 181 serious adverse events were reported in total, 95 (52%) in the sorafenib group and 86 (48%) in the placebo group. Three deaths occurred in each group that were attributed to DEB-TACE. Four deaths were attributed to study drug; three in the sorafenib group and one in the placebo group.INTERPRETATION: The addition of sorafenib to DEB-TACE does not improve progression-free survival in European patients with hepatocellular carcinoma. Alternative systemic therapies need to be assessed in combination with TACE to improve patient outcomes.FUNDING: Bayer PLC and BTG PLC.

Background Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2).Fig. 1Progression-free survivalFig. 2Overall survival Conclusion Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. However, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated.

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.

BACKGROUND: Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9-item Patient Health Questionnaire (PHQ-9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ-9 as a screening instrument for major depressive disorder (MDD) in patients with cancer. METHODS: Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ-9 and a 2-stage procedure to identify cases of MDD. Performance of the PHQ-9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis. RESULTS: Data were available on 4264 patients. When scored as a continuous measure, the PHQ-9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93-0.95). A cutoff score of ≥8 provided a sensitivity of 93% (95% CI, 89%-95%), a specificity of 81% (95% CI, 80%-82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ-9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%-57%), a specificity of 96% (95% CI, 95%-97%), a PPV of 52%, and an NPV of 97%. CONCLUSIONS: The PHQ-9 scored as a continuous measure with a cutoff score of ≥8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population. Cancer 2011. © 2010 American Cancer Society.

Background There is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx; 130 mg/m2, day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m2, day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx. Patients and methods Retrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied. Results Overall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54%; grade 2, 35% and 32%; grade 3, 16% and 3%; grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment. Conclusion Incidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.

Palliative chemotherapy for inoperable/metastatic oesophageal cancer has limited activity. This study assesses the feasibility and activity of gemcitabine and cisplatin in this group of patients. In total, 42 patients with locally advanced/metastatic squamous or adenocarcinoma of the oesophagus were treated with gemcitabine 1250 mg m(-2) days 1 and 8 and cisplatin 75 mg m(-2) day 1 in a 21-day cycle. Interim safety analysis was carried out after the first 19 patients suggested significant toxicity. The dose of gemcitabine was subsequently reduced to 1000 mg m(-2). Patients were assessed for toxicity and response. The median number of treatment cycles per patient was 4 (range 1-6). Grade 3-4 neutropenia occurred in 37% of cycles; however, there was only one episode of neutropenic fever. Nonhaematological toxicities included fatigue, nausea and vomiting. Among 32 patients eligible for response, there were three complete responses and 16 partial responses (overall response rate of 45%); nine patients had stable disease. Median survival was 11 months. The response rate appears to be greatest in those with squamous carcinoma compared to adenocarcinoma (71 vs 33%, P=0.036). The combination of gemcitabine and cisplatin in this schedule has manageable toxicity and significant activity in patients with locally advanced/metastatic oesophageal cancer and is worthy of further study.

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended.

4006 Background: Despite improvements in multidisciplinary management, BTC has a poor outcome. Approximately 20% of cases are suitable for surgical resection with a 5 year survival of < 10%. BILCAP aimed to determine whether capecitabine (Cape) improves overall survival (OS) compared to observation (Obs) following radical surgery. Methods: Patients with completely-resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, haematological and liver function, and ECOG PS ≤2, were randomized 1:1 to Cape (1250 mg/m2 D1-14 every 21 days, for 8 cycles) or Obs. Randomization was minimized on tumor site, resection status, ECOG PS and surgical center. The primary outcome was OS in the intention to treat (ITT) population. 410 patients were needed to detect a hazard ratio (HR) of 0.69 (2-sided α = 0.05 and 80% power). HR was estimated by Cox survival model with adjustment for the minimization factors. Primary analysis performed with at least 24 months (m) follow-up. Results: 447 participants were randomized to Cape (n = 223) or Obs (n = 224) from 44 UK sites between 2006-2014. Median age was 63y (IQR 55, 69) and 201 (45%), 232 (52%), and 14 (3%) patients were ECOG PS 0, 1 and 2 respectively. Primary site: 84 (19%) intrahepatic, 128 (28%) hilar, 156 (35%) extrahepatic CCA and 79 (18%) muscle-invasive gallbladder cancers. Resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. Follow up was at least 36m in > 80% of surviving patients. By ITT analysis (n = 447), median OS was 51m (95%CI 35, 59) for Cape and 36m (95%CI 30, 45) for Obs, HR 0.80 (95%CI 0.63, 1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55, 0.92 p < 0.01). In the per-protocol analysis (Cape n = 210, Obs n = 220) median OS was 53m (95%CI 40, NR) for Cape and 36m (95%CI 30, 44) for Obs, HR 0.75 (95%CI 0.58, 0.97; p = 0.028). Median RFS (ITT) was 25m (95%CI 19, 37) for Cape and 18m (95%CI 13, 28) for Obs. Grade 3-4 toxicity was less than anticipated. Conclusions: Cape improves OS in BTC when used as adjuvant and should become standard of care. Clinical trial information: ISRCTN72785446.

4089 Background: In the CLARINET core study, lanreotide Autogel (LAN) 120 mg deep sc monthly significantly improved PFS vs PBO in metastatic grade-1/2 enteropancreatic NETs. An interim analysis of patients with stable disease (SD) in the core study continuing LAN in the open-label extension (OLE, of which safety was primary objective) showed continued antitumor effects. Here, we report final LAN PFS analyses for subgroups according to tumor origin and prior therapy. Methods: In the core study, patients with metastatic well/moderately differentiated non-functioning (N-F) enteropancreatic NETs, Ki-67

Background Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited. Methods We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptorpositive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of

The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic β2-agonist and an appetite stimulant in patients with cancer cachexia. Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 μg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥4 % or function ≥10 %. Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p = 0.012; right 1.02 vs. 1.06 L, p = 0.004). There was a trend towards an increase in quadriceps and handgrip strength (p > 0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p = 0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

BACKGROUND: Fatigue is associated with cancer and its treatment but we know little about how many and which patients suffer fatigue of clinical severity. We aimed to determine the prevalence of clinically relevant fatigue (CRF) and its associations in outpatients with various cancer diagnoses. PATIENTS AND METHODS: A survey of outpatients with colorectal, breast, gynaecological, genitourinary, sarcoma, melanoma and miscellaneous tumours at a regional cancer centre. Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) fatigue subscale and the Hospital Anxiety and Depression Scale (HADS). These self-report data were linked to demographic and clinical variables. Data were available on 2867 outpatients. RESULTS: The prevalence of CRF (EORTC fatigue subscale > or =40) was 32% (95% confidence interval 31-34%). The variables independently associated with CRF were primary cancer site, having disease present, type of cancer treatment and emotional distress (total HADS score > or =15). Emotional distress had the strongest association with fatigue but half the cases of CRF were not distressed. CONCLUSION: CRF is common in cancer outpatients and is associated with type of disease and treatment, as well as with emotional distress. The association between CRF and emotional distress is strong but they are not equivalent conditions.

Background Oesophageal cancer is a major clinical problem with a generally poor prognosis. As a result there has been interest in combining surgery with neoadjuvant chemotherapy to try and improve outcomes, although the current evidence for benefit is inconsistent. We aimed to compare, in a non-randomised study, the post-operative complication rate and short and long-term survival of patients who underwent surgical resection for carcinoma of the oesophagus and types I and II carcinoma of the oesophago-gastric junction with or without neo-adjuvant chemotherapy. Methods Details of all resections for oesophageal/junctional (types I and II) adenocarcinoma or squamous cell carcinoma between April 2000 and July 2006 were collected prospectively. Data from patients with T3 and/or N1 disease who underwent either neoadjuvant chemotherapy (NAC) or not (non-NAC) were compared. Data were analysed using Kaplan-Meier plots, Mann-Whitney U-test, Cox Regression modelling, and Chi-squared test with Yates' correction where sample sizes

To: (1) estimate the prevalence of clinically significant emotional distress in patients attending a cancer outpatient department and (2) determine the associations between distress and demographic and clinical variables, we conducted a survey of outpatients attending selected clinics of a regional cancer centre in Edinburgh, UK. Patients completed the Hospital Anxiety and Depression Scale (HADS) on touch-screen computers and the scores were linked to clinical variables on the hospital database. Nearly one quarter of the cancer outpatients 674 out of 3071 (22%; 95% confidence interval (CI) 20-23%) met our criterion for clinically significant emotional distress (total HADS score 15 or more). Univariate analysis identified the following statistically significant associations: age < 65, female gender, cancer type and extent of disease. Multivariate analysis indicated that age < 65 (odds ratio 1.41; 95% CI 1.18-1.69), female gender (odds ratio 1.58; 95% CI 1.31-1.92) and active disease (odds ratio 1.72; 95% CI 1.43-2.05) but not cancer diagnosis, were the independent predictors of clinically significant emotional distress. Services to treat distress in cancer patients should be organised to target patients by characteristics other than their cancer diagnosis.

e15180 Background: CLARINET showed LAN 120 mg significantly increased PFS vs PBO (hazard ratio [HR] for progressive disease [PD]/death 0.47 [95% CI: 0.30, 0.73]) in metastatic intestinal and pancre...

e15181 Background: CLARINET was a large 96-week phase 3 study showing that LAN 120 mg significantly improved progression-free survival vs PBO in patients with intestinal and pancreatic NETs. Here, ...

4104 Background: In CLARINET, progression-free survival (PFS) was significantly prolonged with the somatostatin analog LAN 120 mg vs. placebo in patients with metastatic grade 1 or 2 (Ki-67

e15177 Background: The somatostatin analog LAN 120 mg significantly prolonged progression-free survival (PFS) vs. placebo (PBO) in patients with metastatic grade 1 or 2 (Ki-67

e15182 Background: CLARINET showed antitumor effects with LAN 120 mg in metastatic intestinal/pancreatic NETs. Here, we characterize treatment effects within subgroups defined post hoc by baseline ...

233 Background: The prognosis for patients with metastatic pNETs is generally poor and current treatment options can be complicated by safety considerations. In CLARINET, progression-free survival (PFS) was significantly prolonged with the somatostatin analog LAN 120 mg vs. placebo (PBO) in patients with metastatic grade 1 or 2 (Ki-67 25%, 95% had stable disease, 77% had received no previous treatment, and 38% had had previous surgery on the tumor. Median PFS in the pNET subgroup was not reached at study end with LAN vs. 12.1 months [95% CI: 9.4, 18.3] with PBO (HR for PD/death: 0.58 [0.32, 1.04]). (Median PFS for LAN at first planned analysis in the open-label extension study was 29.7 months [12.0, 32.4].) The incidence of adverse events (AEs) in the core study was 88% with both LAN and PBO, and the most common AE was diarrhea (LAN, 43%; PBO, 37%). Treatment-related AEs occurred in 55% of the LAN group and 24% of the PBO group. Serious AEs (SAEs) occurred in 29% vs. 43%, respectively; only three of these patients had treatment-related SAEs (two with LAN, one with PBO). Two patients in each group had AEs leading to withdrawal. Conclusions: The evidence in the pNET subgroup suggesting antitumor effects with LAN together with the favorable long-term safety profile support a positive benefit:risk profile for LAN as a first-line treatment for pNETs. Clinical trial information: NCT00353496.

High-intermediate grade non-Hodgkin's lymphoma (NHL) is an aggressive form of the disease, which can respond well to combination chemotherapy, with long-term survival seen in 40-50% of patients. When NHL relapses following standard treatment, high-dose chemotherapy with peripheral blood stem cell or bone marrow support may still cure a significant proportion of patients. Despite a significant rise in the incidence of NHL over recent years, there remains only limited published economic study concerning the overall lifetime cost of treatment, the cost effectiveness of specific treatments or the overall societal cost burden of the disease. The majority of studies identified for the purposes of this review considered the cost of alternative forms of chemotherapy and bone marrow support strategies for patients with advanced disease. Data from these studies suggest that there is a definite trend towards reduced costs for high-dose therapy, possibly reflecting increasing technical experience and improved bone marrow recovery through the use of stem cell transplantation and growth factors. The limited number of cost-effectiveness evaluations suggest that high-dose therapy, following a chemosensitive relapse, is likely to be considered favourable against commonly quoted cost-effectiveness thresholds. Cost effectiveness is becoming an increasingly important factor to consider in the formal assessment of new interventions conducted by groups such as the UK National Institute for Clinical Excellence. In light of the increasing incidence of NHL and the extended use of high-dose treatments in other subgroups of patients, there is a need for increased research into the economics of new interventions for NHL.

Aim: QoL in patients with gastroenteropancreatic-NETs can be affected by the symptom burden, but also treatment efficacy and safety. To better evaluate this, the EORTC developed a NET-specific QoL questionnaire (QLQ-GI.NET21), to be used in combination with its more generic questionnaire, EORTC QLQ-C30. Here, we examine the impact of LAN vs. placebo on QoL from the CLARINET study. Methods: CLARINET was a 96-week randomized double-blind phase III study, in which patients with well/moderately differentiated, non-functioning EP-NETs were treated with LAN 120 mg (n = 101) or placebo (n = 103) deep SC injections every 4 weeks (NCT00353496). The primary endpoint was progression-free survival (PFS). Safety was a key secondary endpoint. QoL (also a secondary endpoint) was assessed at each study visit using the EORTC QLQ-C30 and the EORTC QLQ-GI.NET21. Results: LAN significantly prolonged PFS vs. placebo (stratified log rank, p = 0.0002; hazard ratio 0.47 [95% CI: 0.30, 0.73]). Treatment-related adverse events (AEs) occurred in 50% of patients in the LAN group vs. 28% in the placebo group. Gastrointestinal disorders were the most common AEs (37% vs. 19%). The QLQ-C30 global health status scores and the QLQ-GI.NET21 endocrine and gastrointestinal subscale scores were similar in the two treatment groups at baseline and throughout treatment, though inter-individual variation was high (Table). Results for the other subscale scores of the QLQ-C30 and QLQ-GI.NET21 questionnaires were also similar between LAN and placebo. Conclusions: Overall, patients on LAN 120 mg had a significantly improved PFS and a good safety/tolerability profile that did not compromise patients' QoL vs. placebo. Further analyses are ongoing to evaluate QoL based on patient characteristics and treatment response. Table: Effect of LAN treatment on patients' QoL. Values are mean (SD); LVA, last post-baseline value available Data shown are for the transformed scores, which can range from 0 to 100. A higher transformed score for global health status represents a better QoL. A higher transformed score for Endocrine and GI symptoms represents a higher level of symptomatology/problems Baseline Week 48 Week 96 LVA QLQ-C30 Global health status/QoL LAN 70.2 (19.9) [n = 98] 70.9 (17.3) [n = 71] 66.4 (22.1) [n = 57] 64.5 (23.2) [n = 98] Placebo 73.6 (19.6) [n = 99] 72.0 (14.9) [n = 59] 70.1 (22.2) [n = 34] 67.0 (22.4) [n = 102] QLQ-GI.NET21 Endocrine symptoms LAN 10.9 (15.0) [n = 98] 11.0 (15.5) [n = 71] 11.1 (15.1) [n = 56] 11.7 (14.9) [n = 97] Placebo 12.0 (16.9) [n = 98] 13.2 (18.0 [n = 48] 11.8 (11.3) [n = 34] 13.9 (19.0) [n = 102] QLQ-GI.NET21 Gastrointestinal symptoms LAN 17.1 (16.4) [n = 98] 19.9 (17.6) [n = 71] 15.3 (13.8) [n = 56] 18.2 (16.5) [n = 97] Placebo 18.3 (18.0) [n = 98] 16.0 (14.3) [n = 58] 17.4 (17.3) [n = 34] 19.8 (18.5) [n = 102] Disclosure: P. Ruszniewski: Ipsen: Consultant/advisory role; honoraria; research funding; partner is Ipsen employee. Novartis: honoraria and research funding; M. Caplin: IPSEN: honoraria for consultant/advisory role. NOVARTIS: Consulting fee, Advisory Committees or Review Panels; LEXICON: Consulting fee, Advisory Committees or Review Panel; M. Pavel: Ipsen: Consulting & Speaker role fee. Pfizer, Inc.: Consulting & Speaker role fee. Novartis Pharmaceuticals: Consulting & Speaker role fee, research funding. Lexicon Pharmaceuticals, Inc.: Consulting & Speaker role fee; J. Cwikla: Ipsen: Research Funding; A. Phan: Ipsen: Research Funding; M. Raderer: Speaker fee from: Ipsen, Novartis Pharmaceuticals, Roche Pharmaceuticals, Pfizer, Inc., Bayer, Inc., Celgene; G. Cadiot: Ipsen: Consultant and Speaker fee. Novartis Pharmaceuticals: Consultant and Speaker fee. Keocyt: Consultant and Speaker fee; G. Rindi: Ipsen: Consultant and Speaker fee. Novartis Pharmaceuticals: Consultant and Speaker fee. Pfizer, Inc.: Consultant and Speaker fee. Advanced Accelerator Applications: Consultant fee; A. Langley: Ipsen: Consultant fee; J. Blumberg: Ipsen: employee; E. Gomez-Panzani: Ipsen: employee. All other authors have declared no conflicts of interest.

4107^ Background: The CLARINET core study showed that the long-acting somatostatin analog (SSA) LAN 120 mg significantly prolonged PFS vs placebo (PBO) in patients (pts) with metastatic enteropancr...

4081 Background: Most 1st-line combination chemotherapy regimens in pts with advanced GC include 5-FU. Taxanes are also active agents in GC, either alone or in combination. However, there is no recognized 2nd-line regimen for use in pts with advanced GC. DJ-927 is a semi-synthetic novel taxane with in vitro activity against GC cells lines. It is administered orally, with hematologic dose-limiting toxicity (DLT) in Phase I studies. The primary objective of this study was to determine the objective response rate of DJ-927 as 2nd-line therapy in pts with advanced GC. Methods: Eligible pts had confirmed advanced GC with no more than 1 prior systemic 5-FU-containing regimen for advanced disease, with adequate hematologic, renal and liver function, and with measurable disease. The starting dose in the 1st cohort of 6 pts was 27 mg/m2 orally, every 3 weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at the optimal dose level. Measurable disease was assessed after every 2 courses. Pharmacokinetic sampling was performed during course 1 only. Sample size based on a 3-outcome 1-stage design was calculated to be 27 pts evaluable for response, with ≥ 4 responses of 27 pts indicating that DJ-927 has activity in advanced GC. Results: 36 pts (male=25; female = 11), KPS ≥ 60%, with GC (n = 23) or OG junction cancer (n = 13), received 104 courses (median = 2; range 1–9) of DJ-927. 2 DLTs (febrile neutropenia; Grade 4 neutropenia > 5 days) occurred at 35 mg/m2, and the optimal starting dose was confirmed as 27 mg/m2. 6 of 36 pts were not evaluable for response (< 1 complete treatment course) due to early disease progression (3), toxicity (2), and drug not given (1). Response data is available for 26 of 30 evaluable pts with confirmed PR (n = 5), SD (15), and PD (6). Toxicity, ≥ grade 3, in evaluable pts (n = 33) included neutropenia (17), anemia (5), thrombocytopenia (4), diarrhoea (7), fatigue (5), lethargy (4), neutropenic sepsis (5). Conclusions: DJ-927 has modest activity in pts with GC who have failed a 5-FU non-taxane based regimen. Toxicities include neutropenia ± sepsis, diarrhoea and lethargy. Further studies of DJ-927 in combination with other active agents are warranted in pts with GC. [Table: see text]

4034 Background: Current cisplatin based regimens for the treatment of AEC are disappointing with response rates between 25 and 45% and median survival of around 9 months. Gemcitabine (Gem) is active against a range of tumour types. Preclinical models suggest synergistic cytotoxic activity for Gem and Cisplatin (Cis), and in phase II trials this combination is active in NSCLC, head & neck cancer and bladder cancer. Methods: This non-randomised open label phase II study evaluated the efficacy and safety of Gem 1250 mg/m2 on days 1, 8, and Cis 75 mg/m2 on day 1 every 21 days in AEC. Patients with; histologically proven, bidimensionally measurable, locally advanced or metastatic oesophageal carcinoma (squamous or adenocarcinoma), aged >18yrs, with a performance status 0–2 and life expectancy >3 months, and able to give informed consent were eligible. Interim review after 19 patients were enrolled suggested that this was unacceptably toxic, subsequent patients were treated with Gem 1000mg/m2 and Cis 75mg/m2. ...